Immune regulation of the unfolded protein response at the mucosal barrier in viral infection
Identifieur interne : 000891 ( Pmc/Corpus ); précédent : 000890; suivant : 000892Immune regulation of the unfolded protein response at the mucosal barrier in viral infection
Auteurs : Ran Wang ; Md. Moniruzzaman ; Eric Shuffle ; Rohan Lourie ; Sumaira Z. HasnainSource :
- Clinical & Translational Immunology [ 2050-0068 ] ; 2018.
Abstract
Protein folding in the endoplasmic reticulum (
Url:
DOI: 10.1002/cti2.1014
PubMed: 29632667
PubMed Central: 5881172
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Immune regulation of the unfolded protein response at the mucosal barrier in viral infection</title><author><name sortKey="Wang, Ran" sort="Wang, Ran" uniqKey="Wang R" first="Ran" last="Wang">Ran Wang</name><affiliation><nlm:aff id="cti21014-aff-0001"></nlm:aff></affiliation><affiliation><nlm:aff id="cti21014-aff-0002"></nlm:aff></affiliation></author><author><name sortKey="Moniruzzaman, Md" sort="Moniruzzaman, Md" uniqKey="Moniruzzaman M" first="Md." last="Moniruzzaman">Md. Moniruzzaman</name><affiliation><nlm:aff id="cti21014-aff-0001"></nlm:aff></affiliation><affiliation><nlm:aff id="cti21014-aff-0002"></nlm:aff></affiliation></author><author><name sortKey="Shuffle, Eric" sort="Shuffle, Eric" uniqKey="Shuffle E" first="Eric" last="Shuffle">Eric Shuffle</name><affiliation><nlm:aff id="cti21014-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Lourie, Rohan" sort="Lourie, Rohan" uniqKey="Lourie R" first="Rohan" last="Lourie">Rohan Lourie</name><affiliation><nlm:aff id="cti21014-aff-0001"></nlm:aff></affiliation><affiliation><nlm:aff id="cti21014-aff-0003"></nlm:aff></affiliation></author><author><name sortKey="Hasnain, Sumaira Z" sort="Hasnain, Sumaira Z" uniqKey="Hasnain S" first="Sumaira Z" last="Hasnain">Sumaira Z. Hasnain</name><affiliation><nlm:aff id="cti21014-aff-0001"></nlm:aff></affiliation><affiliation><nlm:aff id="cti21014-aff-0002"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">29632667</idno><idno type="pmc">5881172</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5881172</idno><idno type="RBID">PMC:5881172</idno><idno type="doi">10.1002/cti2.1014</idno><date when="2018">2018</date><idno type="wicri:Area/Pmc/Corpus">000891</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000891</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Immune regulation of the unfolded protein response at the mucosal barrier in viral infection</title><author><name sortKey="Wang, Ran" sort="Wang, Ran" uniqKey="Wang R" first="Ran" last="Wang">Ran Wang</name><affiliation><nlm:aff id="cti21014-aff-0001"></nlm:aff></affiliation><affiliation><nlm:aff id="cti21014-aff-0002"></nlm:aff></affiliation></author><author><name sortKey="Moniruzzaman, Md" sort="Moniruzzaman, Md" uniqKey="Moniruzzaman M" first="Md." last="Moniruzzaman">Md. Moniruzzaman</name><affiliation><nlm:aff id="cti21014-aff-0001"></nlm:aff></affiliation><affiliation><nlm:aff id="cti21014-aff-0002"></nlm:aff></affiliation></author><author><name sortKey="Shuffle, Eric" sort="Shuffle, Eric" uniqKey="Shuffle E" first="Eric" last="Shuffle">Eric Shuffle</name><affiliation><nlm:aff id="cti21014-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Lourie, Rohan" sort="Lourie, Rohan" uniqKey="Lourie R" first="Rohan" last="Lourie">Rohan Lourie</name><affiliation><nlm:aff id="cti21014-aff-0001"></nlm:aff></affiliation><affiliation><nlm:aff id="cti21014-aff-0003"></nlm:aff></affiliation></author><author><name sortKey="Hasnain, Sumaira Z" sort="Hasnain, Sumaira Z" uniqKey="Hasnain S" first="Sumaira Z" last="Hasnain">Sumaira Z. Hasnain</name><affiliation><nlm:aff id="cti21014-aff-0001"></nlm:aff></affiliation><affiliation><nlm:aff id="cti21014-aff-0002"></nlm:aff></affiliation></author></analytic><series><title level="j">Clinical & Translational Immunology</title><idno type="eISSN">2050-0068</idno><imprint><date when="2018">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Abstract</title><p>Protein folding in the endoplasmic reticulum (<styled-content style="fixed-case" toggle="no">ER</styled-content>) is subject to stringent quality control. When protein secretion demand exceeds the protein folding capacity of the <styled-content style="fixed-case" toggle="no">ER</styled-content>, the unfolded protein response (<styled-content style="fixed-case" toggle="no">UPR</styled-content>) is triggered as a consequence of <styled-content style="fixed-case" toggle="no">ER</styled-content> stress. Due to the secretory function of epithelial cells, <styled-content style="fixed-case" toggle="no">UPR</styled-content> plays an important role in maintaining epithelial barrier function at mucosal sites. <styled-content style="fixed-case" toggle="no">ER</styled-content> stress and activation of the <styled-content style="fixed-case" toggle="no">UPR</styled-content> are natural mechanisms by which mucosal epithelial cells combat viral infections. In this review, we discuss the important role of <styled-content style="fixed-case" toggle="no">UPR</styled-content> in regulating mucosal epithelium homeostasis. In addition, we review current insights into how the <styled-content style="fixed-case" toggle="no">UPR</styled-content> is involved in viral infection at mucosal barriers and potential therapeutic strategies that restore epithelial cell integrity following acute viral infections via cytokine and cellular stress manipulation.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI><pmc article-type="review-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Clin Transl Immunology</journal-id><journal-id journal-id-type="iso-abbrev">Clin Transl Immunology</journal-id><journal-id journal-id-type="doi">10.1002/(ISSN)2050-0068</journal-id><journal-id journal-id-type="publisher-id">CTI2</journal-id><journal-title-group><journal-title>Clinical & Translational Immunology</journal-title></journal-title-group><issn pub-type="epub">2050-0068</issn><publisher><publisher-name>John Wiley and Sons Inc.</publisher-name><publisher-loc>Hoboken</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">29632667</article-id><article-id pub-id-type="pmc">5881172</article-id><article-id pub-id-type="doi">10.1002/cti2.1014</article-id><article-id pub-id-type="publisher-id">CTI21014</article-id><article-categories><subj-group subj-group-type="overline"><subject>Special Feature Review</subject></subj-group><subj-group subj-group-type="heading"><subject>Special Feature Reviews</subject></subj-group></article-categories><title-group><article-title>Immune regulation of the unfolded protein response at the mucosal barrier in viral infection</article-title><alt-title alt-title-type="left-running-head">R Wang <italic>et al</italic>.</alt-title></title-group><contrib-group><contrib id="cti21014-cr-0001" contrib-type="author"><name><surname>Wang</surname><given-names>Ran</given-names></name><xref ref-type="aff" rid="cti21014-aff-0001"><sup>1</sup></xref><xref ref-type="aff" rid="cti21014-aff-0002"><sup>2</sup></xref></contrib><contrib id="cti21014-cr-0002" contrib-type="author"><name><surname>Moniruzzaman</surname><given-names>Md.</given-names></name><xref ref-type="aff" rid="cti21014-aff-0001"><sup>1</sup></xref><xref ref-type="aff" rid="cti21014-aff-0002"><sup>2</sup></xref></contrib><contrib id="cti21014-cr-0003" contrib-type="author"><name><surname>Shuffle</surname><given-names>Eric</given-names></name><xref ref-type="aff" rid="cti21014-aff-0001"><sup>1</sup></xref></contrib><contrib id="cti21014-cr-0004" contrib-type="author"><name><surname>Lourie</surname><given-names>Rohan</given-names></name><xref ref-type="aff" rid="cti21014-aff-0001"><sup>1</sup></xref><xref ref-type="aff" rid="cti21014-aff-0003"><sup>3</sup></xref></contrib><contrib id="cti21014-cr-0005" contrib-type="author" corresp="yes"><name><surname>Hasnain</surname><given-names>Sumaira Z</given-names></name><xref ref-type="aff" rid="cti21014-aff-0001"><sup>1</sup></xref><xref ref-type="aff" rid="cti21014-aff-0002"><sup>2</sup></xref><address><email>sumaira.hasnain@mater.uq.edu.au</email></address></contrib></contrib-group><aff id="cti21014-aff-0001"><label><sup>1</sup></label><named-content content-type="organisation-division">Translational Research Institute</named-content><institution>Immunopathology Group at Mater Research Institute – The University of Queensland</institution><city>Brisbane</city><named-content content-type="country-part">QLD</named-content><country country="AU">Australia</country></aff><aff id="cti21014-aff-0002"><label><sup>2</sup></label><named-content content-type="organisation-division">Faculty of Medicine</named-content><institution>The University of Queensland</institution><city>Brisbane</city><named-content content-type="country-part">QLD</named-content><country country="AU">Australia</country></aff><aff id="cti21014-aff-0003"><label><sup>3</sup></label><named-content content-type="organisation-division">Translational Research Institute</named-content><institution>Inflammatory Bowel Disease Group at Mater Research Institute – The University of Queensland</institution><city>Brisbane</city><named-content content-type="country-part">QLD</named-content><country country="AU">Australia</country></aff><author-notes><corresp id="correspondenceTo"><label>*</label><bold>Correspondence</bold><break></break>SZ Hasnain, Translational Research Institute, Level 4/37 Kent St, Woolloongabba, Brisbane, QLD 4102, Australia.<break></break>E‐mail: <email>sumaira.hasnain@mater.uq.edu.au</email><break></break></corresp></author-notes><pub-date pub-type="epub"><day>03</day><month>4</month><year>2018</year></pub-date><pub-date pub-type="collection"><year>2018</year></pub-date><volume>7</volume><issue>4</issue><issue-id pub-id-type="doi">10.1002/cti2.2018.7.issue-4</issue-id><elocation-id>e1014</elocation-id><history><date date-type="received"><day>04</day><month>12</month><year>2017</year></date><date date-type="rev-recd"><day>28</day><month>2</month><year>2018</year></date><date date-type="accepted"><day>01</day><month>3</month><year>2018</year></date></history><permissions><pmc-comment> © 2018 Australasian Society for Immunology Inc. </pmc-comment>
<copyright-statement content-type="article-copyright">© 2018 The Authors. <italic>Clinical & Translational Immunology</italic> published by John Wiley & Sons Australia, Ltd on behalf of Australasian Society for Immunology Inc.</copyright-statement><license license-type="creativeCommonsBy"><license-p>This is an open access article under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link> License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="file:CTI2-7-e1014.pdf"></self-uri><abstract id="cti21014-abs-0001"><title>Abstract</title><p>Protein folding in the endoplasmic reticulum (<styled-content style="fixed-case" toggle="no">ER</styled-content>) is subject to stringent quality control. When protein secretion demand exceeds the protein folding capacity of the <styled-content style="fixed-case" toggle="no">ER</styled-content>, the unfolded protein response (<styled-content style="fixed-case" toggle="no">UPR</styled-content>) is triggered as a consequence of <styled-content style="fixed-case" toggle="no">ER</styled-content> stress. Due to the secretory function of epithelial cells, <styled-content style="fixed-case" toggle="no">UPR</styled-content> plays an important role in maintaining epithelial barrier function at mucosal sites. <styled-content style="fixed-case" toggle="no">ER</styled-content> stress and activation of the <styled-content style="fixed-case" toggle="no">UPR</styled-content> are natural mechanisms by which mucosal epithelial cells combat viral infections. In this review, we discuss the important role of <styled-content style="fixed-case" toggle="no">UPR</styled-content> in regulating mucosal epithelium homeostasis. In addition, we review current insights into how the <styled-content style="fixed-case" toggle="no">UPR</styled-content> is involved in viral infection at mucosal barriers and potential therapeutic strategies that restore epithelial cell integrity following acute viral infections via cytokine and cellular stress manipulation.</p></abstract><abstract abstract-type="graphical" id="cti21014-abs-0002"><p>We review current insights into how the UPR is involved in viral infection at mucosal barriers and potential therapeutic strategies that restore epithelial cell integrity following acute viral infections via cytokine and cellular stress manipulation.<boxed-text position="anchor" content-type="graphic" id="cti21014-blkfxd-0001" orientation="portrait"><graphic xlink:href="CTI2-7-e1014-g006.jpg" position="anchor" id="nlm-graphic-1" orientation="portrait"></graphic></boxed-text></p></abstract><kwd-group kwd-group-type="author-generated"><kwd id="cti21014-kwd-0001">endoplasmic reticulum stress</kwd><kwd id="cti21014-kwd-0002">epithelial cells</kwd><kwd id="cti21014-kwd-0003">mucosal barrier</kwd><kwd id="cti21014-kwd-0004">unfolded protein response</kwd><kwd id="cti21014-kwd-0005">viral infection</kwd></kwd-group><funding-group><award-group id="funding-0001"><funding-source>Mater Foundation</funding-source></award-group><award-group id="funding-0002"><funding-source><institution-wrap><institution>University of Queensland Postdoctoral Fellowship </institution><institution-id institution-id-type="open-funder-registry">10.13039/501100001794</institution-id></institution-wrap></funding-source></award-group><award-group id="funding-0003"><funding-source>Foundation of Research Excellence Grant</funding-source></award-group></funding-group><counts><fig-count count="5"></fig-count><table-count count="1"></table-count><page-count count="15"></page-count><word-count count="8299"></word-count></counts><custom-meta-group><custom-meta><meta-name>source-schema-version-number</meta-name><meta-value>2.0</meta-value></custom-meta><custom-meta><meta-name>cover-date</meta-name><meta-value>2018</meta-value></custom-meta><custom-meta><meta-name>details-of-publishers-convertor</meta-name><meta-value>Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.0 mode:remove_FC converted:16.04.2020</meta-value></custom-meta></custom-meta-group></article-meta></front><body id="cti21014-body-0001"><sec id="cti21014-sec-0001"><title>Introduction</title><p>The endoplasmic reticulum (ER) is a network of branching tubules that extends throughout the cytoplasm of the cell and serves multiple functions. Once protein is translated by ER‐associated ribosomes, it enters into the ER lumen and is folded in a chaperon‐assisted manner. Additional complex modifications occur before the protein is transported to Golgi. Appropriate protein folding and post‐translational modification are crucial for protein function. Aggregated misfolded proteins in the ER cause cellular stress, which if unresolved can lead to cell death. Despite the stringent regulation around protein folding and redundancy within the chaperone‐assisted folding process, both endogenous and exogenous triggers can disrupt the ER homeostasis and increase protein misfolding. These triggers include but are not limited to nutrient deprivation, hypoxia and disruption by chemical inhibitors of polypeptide N‐linked glycosylation (e.g. tunicamycin) or calcium flux (e.g. thapsigargin), oxidative stress and infection. As a result, the ER has evolved a regulatory network, known as the unfolded protein response (UPR), to control the protein folding process. The UPR activation involves three major downstream effects including reduction in protein synthesis to reduce ER load, enhancement of ER protein folding capacity and upregulation of ER‐associated protein degradation (ERAD). If homeostasis is not regained, the UPR will redirect the balance of signalling to favor autophagy or apoptosis. It is increasingly recognised that the evolutionary conserved UPR signalling has an important role in mucosal inflammation and infection. In this review, we discuss the role of the UPR in maintaining mucosal epithelial cell integrity and barrier function and highlight how the UPR is regulated by the host innate immunity.</p></sec><sec id="cti21014-sec-0002"><title>The UPR pathways</title><p>The UPR pathways trigger a complex network of signals via three ER transmembrane stress sensors: inositol‐requiring enzyme 1 α/β (IRE1 α/β, also known as ERN1/2), PKR‐like ER kinase (PERK) and activating transcription factor 6 (ATF6), depicted schematically in Figure <xref rid="cti21014-fig-0001" ref-type="fig">1</xref>. Under homeostatic condition, the ER luminal domains of these sensor proteins are inactive, due to association with glucose regulating protein 78 (GRP78; also known as BiP). GRP78 has a high affinity for misfolded and unfolded proteins: when luminal load of misfolded protein increases, GRP78 is released from the ER stress sensors, which are then free to initiate downstream signalling outside the ER.</p><fig fig-type="Figure" xml:lang="en" id="cti21014-fig-0001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>Unfolded protein response. During <styled-content style="fixed-case" toggle="no">ER</styled-content> stress, the stress sensors dissociate from <styled-content style="fixed-case" toggle="no">GRP</styled-content>78 and transduce signals. Cleaved <styled-content style="fixed-case" toggle="no">ATF</styled-content>6 translocates to the nucleus to regulate the expressions of <styled-content style="fixed-case" toggle="no">UPR</styled-content> target genes. Activation of <styled-content style="fixed-case" toggle="no">IRE</styled-content>1 leads to its phosphorylation and oligomerisation, which induces translation of spliced <styled-content style="fixed-case" toggle="no">XBP</styled-content>1 to facilitate protein folding, while long‐term <styled-content style="fixed-case" toggle="no">IRE</styled-content>1 activation stimulates <styled-content style="fixed-case" toggle="no">RIDD</styled-content> signalling to decrease <styled-content style="fixed-case" toggle="no">ER</styled-content> protein folding load. Finally, activation of <styled-content style="fixed-case" toggle="no">PERK</styled-content> pathway decreases <styled-content style="fixed-case" toggle="no">ER</styled-content> protein load by initiating global translational inhibition through <styled-content style="fixed-case" toggle="no">eIF</styled-content>2α. <styled-content style="fixed-case" toggle="no">ATF</styled-content>4 gene can escape from the translational suppression and translocate to the nucleus to control expressions of <styled-content style="fixed-case" toggle="no">UPR</styled-content> target genes. Moreover, prolonged activation of <styled-content style="fixed-case" toggle="no">UPR</styled-content> leads to the expressions of inflammatory genes as shown by the dotted arrows.</p></caption><graphic id="nlm-graphic-3" xlink:href="CTI2-7-e1014-g001"></graphic></fig><sec id="cti21014-sec-0003"><title>IRE‐1</title><p>The dissociation of GRP78 allows IRE1 dimerisation and activation of C‐terminal endoribonuclease activity, which non‐canonically splices a 26‐base pair intron from the X‐box binding protein 1 (XBP1) mRNA to produce the spliced form of XBP1 (sXBP1). This spliced form of XBP1 then translates into a transcription factor, which further translocates into the nucleus where it induces expression of a wide variety of genes including ER‐associated chaperones and protein folding enzymes to increase ER size and folding capacity. A separate IRE1α‐dependent decay of mRNA (RIDD) pathway is also described (Figure <xref rid="cti21014-fig-0001" ref-type="fig">1</xref>).<xref rid="cti21014-bib-0001" ref-type="ref">1</xref> RIDD degrades mRNAs to ultimately reduce ER load and subsequently reduce the UPR activation. However, with prolonged ER stress IRE1α becomes hyperactive and degrades mRNAs associated with anti‐apoptotic responses, promoting cell death. IRE1β (also known as ERN2) is abundantly expressed by intestine and lung epithelial cells.<xref rid="cti21014-bib-0002" ref-type="ref">2</xref> Compared to IRE1α, the role of IRE1β in the UPR is not very well studied. IRE1β may also be associated with RIDD,<xref rid="cti21014-bib-0003" ref-type="ref">3</xref> which is closely related to intracellular parasite infections and anti‐viral responses at mucosal surface.<xref rid="cti21014-bib-0004" ref-type="ref">4</xref></p></sec><sec id="cti21014-sec-0004"><title>PERK</title><p>Upon dissociation from GRP78, the transmembrane kinase PERK is activated by oligomerisation and autophosphorylation. PERK phosphorylates eukaryotic translation initiation factor 2α (eIF2α), which inhibits ribosome assembly leading to the inhibition of global protein translation, reducing ER load. Although protein translation is halted under ER stress conditions, translation of specific mRNAs is not subject to inhibition. For example, activating transcription factor 4 (ATF4) escapes translation inhibition, which ultimately leads to expression of genes that regulate amino acid metabolism and autophagy (<italic>discussed later</italic>).<xref rid="cti21014-bib-0005" ref-type="ref">5</xref> Activated ATF4 in turn induces expression of GADD34, a phosphatase which regulates eIF2α phosphorylation. Once ER stress is resolved, eIF2α is dephosphorylated by GADD34–protein phosphatase 1 complex to restore global protein synthesis.</p></sec><sec id="cti21014-sec-0005"><title>ATF6</title><p>After sensing misfolding proteins, GRP78 disengages from ATF6α or β isoforms. ATF6 translocates from ER to the Golgi apparatus where it is cleaved by resident proteases sphingosine‐1‐phosphate and sphingosine‐2‐phosphate (S1P and S2P, respectively) to produce a cytosolic ATF6p50 fragment. The ATF6p50 fragment then translocates to the nucleus to modulate gene expression relating to increased ER folding capacity and ERAD pathway activation.<xref rid="cti21014-bib-0006" ref-type="ref">6</xref>, <xref rid="cti21014-bib-0007" ref-type="ref">7</xref></p><p>The three branches of UPR signalling have reasonably distinct downstream functions, but they are engaged in a coordinated fashion and can act together. For example, XBP1 transcription can be induced by ATF6, and increased IRE1α expression is dependent on PERK‐ATF4 pathway,<xref rid="cti21014-bib-0008" ref-type="ref">8</xref> suggesting the complex interplay and cross‐regulation between the three branches of UPR pathway (Figure <xref rid="cti21014-fig-0001" ref-type="fig">1</xref>).</p></sec></sec><sec id="cti21014-sec-0006"><title>Intersection between the UPR and other cellular pathways</title><p>Much of our understanding of the role of the UPR in physiology comes from studies where a specific arm of the UPR has been investigated in isolation or the intersection of this pathway with others has not been taken into account. However, there is growing appreciation of the fact that the UPR is interlinked with and may act in concert with other cellular processes such as oxidative stress, inflammation and autophagy.</p><sec id="cti21014-sec-0007"><title>UPR‐driven autophagy</title><p>Autophagy maintains cellular homeostasis and is involved in MHC class I and II presentation of cytoplasmic and nuclear antigens, which we have reviewed previously.<xref rid="cti21014-bib-0008" ref-type="ref">8</xref> In response to irreversible ER stress, the terminal UPR can activate autophagy to break down the terminally misfolded proteins. During the autophagy process, cellular components are encapsulated within autophagosomes and directed for controlled degradation. Different UPR branches can signal through and induce autophagy, including PERK‐eIF2α as well as IRE1α pathways (Figure <xref rid="cti21014-fig-0001" ref-type="fig">1</xref>). Transcription factor ATF4 that escapes PERK‐associated translation inhibition activates transcription of <italic>CHOP</italic> in cells experiencing persistent ER stress.<xref rid="cti21014-bib-0005" ref-type="ref">5</xref> ATF4 and CHOP can form a heterodimer to activate cellular death pathways and induce expression of a large array of autophagy‐related genes.<xref rid="cti21014-bib-0009" ref-type="ref">9</xref></p><p>Defects in the UPR and autophagy pathways have synergistic effects. XBP1 is crucial in autophagy induction in some settings, for instance protection from neural degeneration.<xref rid="cti21014-bib-0010" ref-type="ref">10</xref> XBP1 deletion induces only mild superficial intestinal inflammation; however, concomitant deletion of XBP1 and epithelial‐associated autophagy‐related protein 7 (ATG7) or ATG16L1 results in more severe ER stress and small intestinal inflammation.<xref rid="cti21014-bib-0011" ref-type="ref">11</xref> Supporting this, human genome wide association studies (GWAS) reveal that polymorphisms in <italic>ATG16L1</italic> gene and defects in autophagy pathways are associated with increased risk of developing Crohn's disease, a form of inflammatory bowel disease leading to chronic inflammation.<xref rid="cti21014-bib-0012" ref-type="ref">12</xref></p><p>Autophagy may also be a mechanism of disposing terminally damaged ER. It was thought to be a non‐specific process, but selective autophagy processes that target specific organelles such as mitochondria have been described. Autophagy of ER in mammalian cells was reported, but detailed mechanisms are still unknown. FAM134B, the selective autophagy receptor for ER turnover, induces selective autophagy of the ER (termed ER‐phagy) in mammalian cells.<xref rid="cti21014-bib-0013" ref-type="ref">13</xref> It has been suggested that FAM134B binds to microtubule‐associated protein 1A/1B‐light chain 3 (LC3) and GABA type A receptor‐associated protein (GABARAP), thereby initiating ER degradation through autophagy.<xref rid="cti21014-bib-0013" ref-type="ref">13</xref></p></sec><sec id="cti21014-sec-0008"><title>Intersection of the UPR and inflammation</title><p>The UPR and inflammation are interconnected on many levels. Defects in protein folding or in any of the individual branches of the UPR spontaneously induce an inflammatory response. In a clinical setting, this has been described particularly in inflammatory bowel disease<xref rid="cti21014-bib-0008" ref-type="ref">8</xref> and lung disease.<xref rid="cti21014-bib-0008" ref-type="ref">8</xref>, <xref rid="cti21014-bib-0014" ref-type="ref">14</xref> Upon sensing pathogen‐associated antigens, pattern recognition receptors (PRRs) including Toll‐like receptors (TLRs) and nucleotide‐binding oligomerisation domain (NOD)‐like receptors can lead to the UPR activation and subsequent inflammation. TLR2 and TLR4 can activate IRE1α with resultant increased sXBP1 required for optimal and sustained production of proinflammatory cytokines in macrophages.<xref rid="cti21014-bib-0011" ref-type="ref">11</xref> NOD1 and NOD2 signalling can trigger the UPR activation and inflammatory cytokine IL‐6 production from macrophages in a murine model of bacterial infection.<xref rid="cti21014-bib-0015" ref-type="ref">15</xref> ER stress and the UPR activation generate reactive oxygen and nitrogen species (ROS/RNS), which modify the redox state of the ER, triggering an inflammatory response.</p><p>The activation of NFκB, key regulator for immunity and inflammatory response, is linked to the UPR. The NFκB inhibitor IκB has a shorter half‐life than NFκB: activation of PERK and concomitant translational inhibition through eIF2α leads to NFκB activation independent of IκB phosphorylation.<xref rid="cti21014-bib-0016" ref-type="ref">16</xref> Also, IRE1α can interact with TNF receptor activating factor 2, which recruits IκB kinase leading to IκB phosphorylation and NFκB activation.<xref rid="cti21014-bib-0017" ref-type="ref">17</xref> It is important to note that ER stress and the UPR have been reported to influence NFκB activation both positively and negatively (Figure <xref rid="cti21014-fig-0001" ref-type="fig">1</xref>). The intensity of ER stress influences NFκB activation status positively;<xref rid="cti21014-bib-0018" ref-type="ref">18</xref> however, preconditioning of cells with low level of ER stress is thought to attenuate NFκB activation.<xref rid="cti21014-bib-0019" ref-type="ref">19</xref></p><p>Conversely, mucosal inflammation modifies ER stress and UPR pathways. Both ROS and RNS produced by innate immune cells during inflammation can activate the UPR in target cells directly. Inflammatory cytokines such as IL‐17A, IFN‐γ and IL‐23 initiate the UPR indirectly via inducing oxidative stress, which inhibits the production of protein disulphide isomerases, that are key components of the endoplasmic reticulum‐assisted folding system (ERAF), resulting in the accumulation of unfolded proteins within the ER and UPR activation.<xref rid="cti21014-bib-0020" ref-type="ref">20</xref> In contrast, cytokines, like IL‐10 and IL‐22, have been shown to suppress ER stress and its associated UPR activation to alleviate inflammation in intestinal mucosal system.<xref rid="cti21014-bib-0021" ref-type="ref">21</xref><sup>,</sup><xref rid="cti21014-bib-0021" ref-type="ref">21</xref> The evolutionary benefit of the ability of cytokines to rapidly stop/start protein synthesis is unclear, but may relate to cellular defences during viral infection, as discussed later.</p></sec></sec><sec id="cti21014-sec-0009"><title>Physiological role of the UPR in maintaining epithelial barrier function</title><p>UPR activation plays important role in mucosal homeostasis. Of note, the UPR is involved in cell differentiation and can also be manipulated to accommodate a change in protein load within cells.<xref rid="cti21014-bib-0021" ref-type="ref">21</xref>, <xref rid="cti21014-bib-0022" ref-type="ref">22</xref> This is important at the mucosal surfaces where secretory cells must produce large amounts of large, complex proteins to maintain the secreted mucus barrier and provide defence against microbes.</p><sec id="cti21014-sec-0010"><title>The UPR activation disrupts intestinal epithelial barrier homeostasis</title><p>The intestinal epithelial barrier forms a selectively permeable immunologically tolerant but alert barrier between the sterile inside and microbe‐laden lumen. Mucins, the major macromolecular component of the mucus layer, are complex, highly glycosylated proteins secreted by goblet cells. Due to high secretory demand, the UPR plays an essential role in maintaining secretory cell homeostasis in the intestine. It is hard to delineate the effects of the UPR in isolation, due to the nature of the intrinsically entwined pathways. Consequently, genetically modified experimental models highlight the importance of the UPR in maintaining homeostasis.</p><p>Multiple animal models show that the UPR can be pathologically activated at several points when key components such as chaperones, transcription factors or key enzymes are absent or attenuated. Deletion of the major UPR transcription factor XBP1 in intestinal epithelial cells causes loss of mature Paneth cells, reduction in goblet cells, impaired bacterial handling and increased sensitivity to dextran sodium sulphate (DSS)‐induced colitis.<xref rid="cti21014-bib-0023" ref-type="ref">23</xref><italic>Ern2</italic><sup><italic>−/−</italic></sup> mice lacking ER‐resident endonuclease, IRE1β, have increased Grp78 levels in intestinal epithelial cells and increased Muc2 misfolding,<xref rid="cti21014-bib-0002" ref-type="ref">2</xref> which lead to increased susceptibility to DSS colitis.<xref rid="cti21014-bib-0024" ref-type="ref">24</xref> Mice deficient in ATF6 have increased expression of ER stress genes and sensitivity to DSS colitis.<xref rid="cti21014-bib-0025" ref-type="ref">25</xref> AGR2 is a protein disulphide isomerase involving in disulphide bond formation in proteins within the ER. <italic>Agr2</italic> knockout mice have increased ER stress and suffer from a spontaneous granulomatous ileocolitis with goblet cell depletion.<xref rid="cti21014-bib-0026" ref-type="ref">26</xref>, <xref rid="cti21014-bib-0027" ref-type="ref">27</xref></p><p>Aside from direct UPR component deficiency, abnormalities in proteins sequence or glycosylation sites also lead to the UPR activation and epithelial cell stress. Single missense mutation in <italic>Muc2</italic> gene leads to misfolding of the major secreted intestinal mucin Muc2, resulting in a strong UPR response and subsequent development of spontaneous colitis characterised by activation of both innate and adaptive immunities with an IL‐23/T<sub>H</sub>17 phenotype.<xref rid="cti21014-bib-0028" ref-type="ref">28</xref>, <xref rid="cti21014-bib-0029" ref-type="ref">29</xref> Immune‐regulated alterations in mucin glycosylation following <italic>Trichuris muris</italic> infection contribute to clearance of parasitic infection.<xref rid="cti21014-bib-0030" ref-type="ref">30</xref></p><p>Besides mucin secretion, a new underappreciated role of goblet cells (GCs) is antigen sampling through the goblet cell‐associated antigen passages (GAPs) under homeostatic conditions.<xref rid="cti21014-bib-0031" ref-type="ref">31</xref> Overriding GC microbial sensing to open colonic GAPs or inappropriate delivery of luminal pathogens through GAPs resulted in the influx of leucocytes and the production of inflammatory cytokines in the setting of normal, non‐pathogenic, microbiota.<xref rid="cti21014-bib-0031" ref-type="ref">31</xref>, <xref rid="cti21014-bib-0032" ref-type="ref">32</xref> This microbial sensing by colonic GCs has a critical role in regulating the exposure of the colonic immune system to luminal substances. Although detailed mechanisms are unknown, it presents an intriguing possibility that GC intrinsic UPR and autophagy pathways may be involved in this antigen trafficking process. Interestingly, as a host defence mechanism, GCs are able to shut off GAPs in response to intrinsic sensing of an invasive pathogen like <italic>Salmonella typhimurium</italic> via MyD88 signalling.<xref rid="cti21014-bib-0033" ref-type="ref">33</xref></p><p>Another secretory cell in the small intestine is the highly specialised Paneth cell, which secretes antimicrobial molecules.<xref rid="cti21014-bib-0034" ref-type="ref">34</xref>, <xref rid="cti21014-bib-0035" ref-type="ref">35</xref> The UPR plays an important role in Paneth cell production of antimicrobial peptides. Paneth cell‐specific <italic>Xbp1</italic> deletion is sufficient to induce ER stress and autophagy, which results in ileitis which is reversible under germ‐free conditions.<xref rid="cti21014-bib-0011" ref-type="ref">11</xref> The importance of Paneth cell secreting antimicrobial peptides is highlighted in the bacterial <italic>S. typhimurium</italic> infection model. The UPR activation and associated autophagy are required to ensure antimicrobial peptide secretion from Paneth cells during infection.<xref rid="cti21014-bib-0036" ref-type="ref">36</xref> Besides the intrinsic UPR activation, extrinsic signals from innate lymphoid cells are also required.<xref rid="cti21014-bib-0036" ref-type="ref">36</xref> The UPR not only regulates Paneth cell homeostasis, but also preserves its antimicrobial peptide secretory function during infections by increasing the UPR activation threshold to limit pathogen dissemination.</p><p>UPR defects within immune cells predispose to inflammation. Lamina propria‐resident dendritic cells (DCs) kill penetrating bacteria by phagocytosis and present bacterial antigens to adaptive T cells. NOD2‐ and ATG16L1‐mediated autophagies are required for DCs to process and present bacteria antigen via major histocompatibility complex (MHC) class II and I to induce CD4<sup> </sup>and CD8 T‐cell response.<xref rid="cti21014-bib-0037" ref-type="ref">37</xref> Individuals carrying <italic>NOD2</italic> and <italic>ATG16L1</italic> polymorphisms display impaired antigen presentation in mucosal DCs and are at increased risk of developing Crohn's disease.<xref rid="cti21014-bib-0038" ref-type="ref">38</xref>, <xref rid="cti21014-bib-0039" ref-type="ref">39</xref> XBP1 is constitutively spliced in DCs, highlighting the importance of consistent UPR activation. Loss of <italic>Xbp1</italic> in haematopoietic lineage cells results in a reduced number of DCs. The impairment can be rescued by overexpression of <italic>Xbp1</italic> in haematopoietic progenitors.<xref rid="cti21014-bib-0040" ref-type="ref">40</xref> Loss of <italic>Xbp1</italic> in CD11c<sup>+</sup> cells leads to defects in phenotype, ER homeostasis and antigen presentation by CD8α<sup>+</sup> conventional DCs. These functional defects result from IRE1α‐dependent degradation of mRNAs, which encode MHC class I machinery in the absence <italic>Xbp1,</italic><xref rid="cti21014-bib-0041" ref-type="ref">41</xref>, <xref rid="cti21014-bib-0042" ref-type="ref">42</xref> again highlighting the crosstalk between the UPR and autophagy. Constant IRE1 pathway activation is not exclusive to DCs: developing B cells and T cells also have constitutive activation of IRE1 without activation of any of the other UPR cascades.<xref rid="cti21014-bib-0043" ref-type="ref">43</xref></p></sec><sec id="cti21014-sec-0011"><title>The UPR in airway epithelial barrier homeostasis</title><p>Similar to intestinal mucosal epithelial cells, lung epithelial cells have developed many defence mechanisms to deal with environmental exposures. Increasing evidence shows that the UPR pathways interact with the recognition and handling of exogenous threats, like viruses.<xref rid="cti21014-bib-0044" ref-type="ref">44</xref> The continuous epithelium in the airways acts as a physical barrier to keep the underlying immune system separated from exogenous air‐borne pathogens. Ciliated cells continuously clear inhaled matter trapped by the mucus layer. Respiratory goblet cells synthesise and secrete the mucins, MUC5B and MUC5AC rather than MUC2. MUC5B/AC, and their glycoforms contribute to the elasticity and viscous nature of the mucus layer covering epithelium.<xref rid="cti21014-bib-0045" ref-type="ref">45</xref> Mice with <italic>Muc5b</italic> deficiency develop spontaneous pulmonary pathology from chronic bacterial infection.<xref rid="cti21014-bib-0046" ref-type="ref">46</xref> Distinctive to MUC5B, production of MUC5AC is often associated with pathogenesis of respiratory diseases such as asthma or lung fibrosis. In human bronchial epithelial cells (HBECs), sXBP1 induced ER expansion and Ca<sup>2+</sup> storage contributes to IL‐8 secretion.<xref rid="cti21014-bib-0047" ref-type="ref">47</xref> IRE1β is expressed in HBECs and is upregulated in cystic fibrosis and asthmatic HBECs. Studies with <italic>Ern2</italic><sup><italic>−/−</italic></sup> mice revealed that IRE1β is required for airway mucin production via the activation of the transcription factor XBP1.<xref rid="cti21014-bib-0048" ref-type="ref">48</xref> In response to ER stress, IRE1β activates its endonuclease activity to repress translation through 28S ribosomal RNA cleavage. IRE1β is abundantly expressed in HBECs;<xref rid="cti21014-bib-0049" ref-type="ref">49</xref> hence, the IRE1β‐dependent mRNA degradation may be important for efficient translational repression in combating ER stress.</p></sec></sec><sec id="cti21014-sec-0012"><title>The immune system dynamically regulates the UPR activation in epithelial cells</title><p>Several endogenous factors can activate the UPR and hence alter the protein load of epithelial/secretory cells. However, whether the immune system can have a direct effect on epithelial cells has received little attention. Some studies have demonstrated that inflammatory cytokines can induce oxidative stress within epithelial cells.<xref rid="cti21014-bib-0050" ref-type="ref">50</xref>, <xref rid="cti21014-bib-0051" ref-type="ref">51</xref>, <xref rid="cti21014-bib-0052" ref-type="ref">52</xref> However, studies have mainly focused on epithelial cell‐derived cytokines and/or chemokines rather than cytokines that affect epithelial cells. We demonstrated that specific inflammatory cytokines initiate ER stress by inducing oxidative stress, while other counteracting cytokines suppress stress and facilitate ER protein folding.<xref rid="cti21014-bib-0053" ref-type="ref">53</xref> While this study focused on pancreatic β‐cells, we have discovered that cytokine regulation of cellular stress is common to multiple epithelial cell types including intestinal and respiratory epithelial cells. In contrast, cytokines, such as IL‐10 and IL‐22, suppress ER stress and UPR activation, leading to increased mucus production, improved barrier function and attenuated intestinal mucosal inflammation in experimental colitis models.<xref rid="cti21014-bib-0052" ref-type="ref">52</xref>, <xref rid="cti21014-bib-0054" ref-type="ref">54</xref></p><p>Immunity regulates protein production and secretion by non‐immune cells by indirectly modulating the UPR (Figure <xref rid="cti21014-fig-0002" ref-type="fig">2</xref>). As an instructive example of the ability of cytokines to modulate protein production, recent studies in our laboratory show that in chronic infection (nematode, <italic>Trichuris muris</italic>), the amount of ER stress and consequent Muc2 biosynthesis is dictated by an intact adaptive immune response (Figure <xref rid="cti21014-fig-0003" ref-type="fig">3</xref>). ER stress occurs in mice that mount a T<sub>H</sub>1/17 response (low‐dose infection), which show goblet cell pathology and fail to clear the infection. However, mice that mount a T<sub>H</sub>2 response (high‐dose infection) show high levels of goblet cell protein biosynthesis and secretion and go on to clear the infection. These data support our hypothesis of specific cytokines modulating protein production. Interestingly, ER stress is not observed in the immunodeficient mice that have chronic <italic>T. muris</italic> infection, strengthening our hypothesis of host intrinsic‐induced cytokines being responsible for the activation of the UPR and induction of ER stress. We suggest that inflammatory cytokines have evolved to disrupt protein biosynthesis in cells prone to viral infection such as mucosal epithelial cells in order to reduce viral replication as a hereto‐unrecognised element of the immune response.</p><fig fig-type="Figure" xml:lang="en" id="cti21014-fig-0002" orientation="portrait" position="float"><label>Figure 2</label><caption><p>Inappropriate activation of stress cycle. Although the production of cytokines such as interferons (type I) is beneficial for anti‐viral responses; however, prolonged production further induces protein misfolding and leads to a cycle of stress and inflammation in the absence of pathogens. These sequential events destroy the epithelial integrity and leave the epithelium vulnerable to other chronic diseases. Therefore, stress‐reducing cytokines such as <styled-content style="fixed-case" toggle="no">IL</styled-content>‐10 can play an important role to minimise protein misfolding and stop stress–inflammation cycle.</p></caption><graphic id="nlm-graphic-5" xlink:href="CTI2-7-e1014-g002"></graphic></fig><fig fig-type="Figure" xml:lang="en" id="cti21014-fig-0003" orientation="portrait" position="float"><label>Figure 3</label><caption><p><styled-content style="fixed-case" toggle="no">ER</styled-content> stress in mucosal nematode infection. C57<styled-content style="fixed-case" toggle="no">BL</styled-content>/6 mice infected with Trichuris muris (<styled-content style="fixed-case" toggle="no">T<sub>H</sub></styled-content>1‐dominant: 15 eggs) or (<styled-content style="fixed-case" toggle="no">T<sub>H</sub></styled-content>2‐dominant and innate: 150 eggs). <bold>(a)</bold> Periodic acid–Schiff staining shows increased protein load within goblet cells, and black arrows indicate the worms. <bold>(b)</bold> Caecal epithelial cell <styled-content style="fixed-case" toggle="no">qRT</styled-content>‐<styled-content style="fixed-case" toggle="no">PCR</styled-content> shows increased <styled-content style="fixed-case" toggle="no">ER</styled-content> stress (<styled-content style="fixed-case" toggle="no">sX</styled-content>bp1) in <styled-content style="fixed-case" toggle="no">T<sub>H</sub></styled-content>1 and negligible <styled-content style="fixed-case" toggle="no">ER</styled-content> stress in <styled-content style="fixed-case" toggle="no">T<sub>H</sub></styled-content>2‐dominated immune response, despite an increase in <bold>(c)</bold> protein load (Muc2). Immunodeficient mice (innate) show no <styled-content style="fixed-case" toggle="no">ER</styled-content> stress despite chronic infection and high protein load. Statistics: <italic>n </italic>= 4–6; <styled-content style="fixed-case" toggle="no">ANOVA</styled-content>, ***<italic>P </italic>< 0.001 vs uninfected (N) mice.</p></caption><graphic id="nlm-graphic-7" xlink:href="CTI2-7-e1014-g003"></graphic></fig><p>Balanced and integrated ER stress and UPR signalling are crucial in maintaining intestinal mucosal homeostasis, and the immune system can either alleviate or aggravate ER stress.<xref rid="cti21014-bib-0055" ref-type="ref">55</xref> IL‐10 produced by regulatory T cells can suppress ER stress by inhibiting the translocation of ATF6p50 to the nucleus and downstream p38 mitogen‐activated protein kinase (MAPK) activation in intestinal epithelial cells.<xref rid="cti21014-bib-0056" ref-type="ref">56</xref> This maintains mucin production in goblet cells, preserving the mucus barrier and reducing further immune activation.<xref rid="cti21014-bib-0054" ref-type="ref">54</xref> Another regulatory‐related cytokine IL‐22 reduces high‐fat diet‐associated oxidative and ER stress in intestinal epithelial cells and subsequent intestinal inflammation to improve mucosal barrier function.<xref rid="cti21014-bib-0052" ref-type="ref">52</xref></p></sec><sec id="cti21014-sec-0013"><title>The UPR in viral replication at mucosal epithelial barriers</title><p>Mucosal epithelial cells, due to their unique location with constant exposure to pathogens, activate different UPR pathways to adapt to the microenvironment and maintain homeostasis. ER stress and UPR activation are mechanisms by which mucosal epithelial cells combat viral infections. Viruses manipulate UPR and host protein synthesis machinery to favor replication. Rather than the chronic UPR activation provoked by inflammation, the UPR pathways are suppressed or bypassed by viruses. Viruses have adapted many ways to hijack the ER to replicate<xref rid="cti21014-bib-0057" ref-type="ref">57</xref>, <xref rid="cti21014-bib-0058" ref-type="ref">58</xref>, <xref rid="cti21014-bib-0059" ref-type="ref">59</xref> and mimic host cytokines/cytokine receptors.<xref rid="cti21014-bib-0060" ref-type="ref">60</xref> Synthesis of viral proteins often involves high levels of misfolding due to the high mutation rate, the unstable nature of viral genomes and extensive glycosylation of viral envelope proteins.<xref rid="cti21014-bib-0061" ref-type="ref">61</xref> Moreover, along with viral protein misfolding, induction of ER Ca<sup>2+</sup> leakage, ER membrane rearrangement and modulation of intracellular glycoprotein trafficking have all been implicated in the UPR response.<xref rid="cti21014-bib-0062" ref-type="ref">62</xref> Therefore, it is not surprising that viral infections often cause ER stress and activation of the UPR.<xref rid="cti21014-bib-0059" ref-type="ref">59</xref>, <xref rid="cti21014-bib-0063" ref-type="ref">63</xref>, <xref rid="cti21014-bib-0064" ref-type="ref">64</xref></p><sec id="cti21014-sec-0014"><title>Viral modulation of the UPR</title><p>Viruses have evolved mechanisms to modulate the UPR to either suppress or exacerbate already existing ER stress in order to maximise viral protein biosynthesis, and reduce or increase inflammation (Figure <xref rid="cti21014-fig-0004" ref-type="fig">4</xref>, Table <xref rid="cti21014-tbl-0001" ref-type="table">1</xref>). Viruses rely on the host ER and the ER stress response to replicate as viral replication is severely diminished in cell lines with mutations in ER‐resident genes.<xref rid="cti21014-bib-0065" ref-type="ref">65</xref> On the one hand, neither human cytomegalovirus nor West Nile virus, interestingly, induce canonical ER stress pathway via induction of XBP1‐associated gene expression, rather they specifically trigger XBP1 for optimal cytokine production.<xref rid="cti21014-bib-0066" ref-type="ref">66</xref> Hepatitis C virus, on the other hand, activates IRE1 but inhibits XBP1 and blocks eIF2α phosphorylation to prevent upregulation of ERAD machinery in order to establish persistency in infected hepatocytes.<xref rid="cti21014-bib-0057" ref-type="ref">57</xref> Some viruses may selectively activate one arm of the UPR while suppressing other branches. Influenza A virus is found to selectively induce ATF6 translocation to promote caspase‐12‐dependent cell apoptosis.<xref rid="cti21014-bib-0067" ref-type="ref">67</xref> The respiratory syncytial virus (RSV) activates a non‐canonical ER stress response with preferential activation of the IRE1 and activated ATF6 pathways without concomitant significant activation of the PERK pathway.<xref rid="cti21014-bib-0068" ref-type="ref">68</xref></p><fig fig-type="Figure" xml:lang="en" id="cti21014-fig-0004" orientation="portrait" position="float"><label>Figure 4</label><caption><p>Virus‐controlled <styled-content style="fixed-case" toggle="no">UPR</styled-content> response. In homeostatic conditions, proteins are correctly folded in the <styled-content style="fixed-case" toggle="no">ER</styled-content> and secreted from cells. However, <styled-content style="fixed-case" toggle="no">ER</styled-content> protein misfolding activates <styled-content style="fixed-case" toggle="no">UPR</styled-content> pathways leading to the degradation of misfolded proteins, autophagy, inflammation and apoptosis. Viruses can directly or indirectly affect the <styled-content style="fixed-case" toggle="no">UPR</styled-content> by selective activation or inhibition of <styled-content style="fixed-case" toggle="no">UPR</styled-content> components (shown with red arrows) through endosomal and cytosolic <styled-content style="fixed-case" toggle="no">PRR</styled-content>s. Viral‐controlled <styled-content style="fixed-case" toggle="no">UPR</styled-content> pathways then ultimately boost the production of viral proteins, while dampening the immune response against the virus.</p></caption><graphic id="nlm-graphic-9" xlink:href="CTI2-7-e1014-g004"></graphic></fig><table-wrap id="cti21014-tbl-0001" xml:lang="en" orientation="portrait" position="float"><label>Table 1</label><caption><p>Viruses capable of modulating the unfolded protein response</p></caption><table frame="hsides" rules="groups"><col style="border-right:solid 1px #000000" span="1"></col><col style="border-right:solid 1px #000000" span="1"></col><col style="border-right:solid 1px #000000" span="1"></col><thead valign="top"><tr style="border-bottom:solid 1px #000000"><th align="left" valign="top" rowspan="1" colspan="1">Name</th><th align="left" valign="top" rowspan="1" colspan="1">Mechanism</th><th align="left" valign="top" rowspan="1" colspan="1">References</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">Influenza A virus</td><td align="left" rowspan="1" colspan="1">Induces ER stress for upregulation of ER‐resident protein ERp57 to facilitate viral protein cleavage</td><td align="left" rowspan="1" colspan="1"><xref rid="cti21014-bib-0084" ref-type="ref">84</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Human cytomegalovirus</td><td align="left" rowspan="1" colspan="1">Encodes a protein, pUL38, which phosphorylates PERK and suppresses IRE1 to prevent cellular apoptosis induced by ER stress, limiting immune detection</td><td align="left" rowspan="1" colspan="1"><xref rid="cti21014-bib-0058" ref-type="ref">58</xref>, <xref rid="cti21014-bib-0066" ref-type="ref">66</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Hepatitis B virus</td><td align="left" rowspan="1" colspan="1">Activates ATF6 and IRE1/sXBP1 pathways of the UPR</td><td align="left" rowspan="1" colspan="1"><xref rid="cti21014-bib-0059" ref-type="ref">59</xref>, <xref rid="cti21014-bib-0085" ref-type="ref">85</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Hepatitis C virus</td><td align="left" rowspan="1" colspan="1">Activates IRE1 but inhibits XBP1 and blocks eIF2α phosphorylation to prevent upregulation of ERAD machinery in order to establish persistency in infected hepatocytes</td><td align="left" rowspan="1" colspan="1"><xref rid="cti21014-bib-0057" ref-type="ref">57</xref>, <xref rid="cti21014-bib-0086" ref-type="ref">86</xref>, <xref rid="cti21014-bib-0087" ref-type="ref">87</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">West Nile virus</td><td align="left" rowspan="1" colspan="1">Induces CHOP (UPR transcription factor) to induce apoptosis</td><td align="left" rowspan="1" colspan="1"><xref rid="cti21014-bib-0088" ref-type="ref">88</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Bovine viral diarrhoea virus</td><td align="left" rowspan="1" colspan="1">Induces CHOP to induce apoptosis</td><td align="left" rowspan="1" colspan="1"><xref rid="cti21014-bib-0063" ref-type="ref">63</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Respiratory syncytial virus</td><td align="left" rowspan="1" colspan="1">Induces caspase‐12‐dependent apoptosis through activating the UPR; Preferential activation of the IRE1 and activated ATF6 pathways with no concomitant significant activation of the PERK pathway</td><td align="left" rowspan="1" colspan="1"><xref rid="cti21014-bib-0068" ref-type="ref">68</xref>, <xref rid="cti21014-bib-0089" ref-type="ref">89</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Dengue virus</td><td align="left" rowspan="1" colspan="1">Activates the UPR to facilitate protein folding but not to induce apoptosis</td><td align="left" rowspan="1" colspan="1"><xref rid="cti21014-bib-0090" ref-type="ref">90</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Japanese encephalitis virus</td><td align="left" rowspan="1" colspan="1">Induces CHOP to induce apoptosis in fibroblasts and neuronal cells</td><td align="left" rowspan="1" colspan="1"><xref rid="cti21014-bib-0091" ref-type="ref">91</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Chikungunya viruses (CHIKV)</td><td align="left" rowspan="1" colspan="1">CHIKV non‐structural protein 4 (nsp4) expression in mammalian cells suppresses eIF2α phosphorylation that regulates the PERK pathway</td><td align="left" rowspan="1" colspan="1"><xref rid="cti21014-bib-0092" ref-type="ref">92</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Severe acute respiratory syndrome coronavirus (SARS‐CoV)</td><td align="left" rowspan="1" colspan="1">The 8ab protein binds directly to the luminal domain of ATF6, the type II ER stress sensor, to induce UPR activation.</td><td align="left" rowspan="1" colspan="1"><xref rid="cti21014-bib-0093" ref-type="ref">93</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">African swine fever virus</td><td align="left" rowspan="1" colspan="1">Maintain eIF2α phosphorylation independent of PERK activation; ASFV is capable of blocking the expression of CHOP</td><td align="left" rowspan="1" colspan="1"><xref rid="cti21014-bib-0094" ref-type="ref">94</xref></td></tr></tbody></table><permissions><copyright-holder>John Wiley & Sons, Ltd</copyright-holder><license><license-p>This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.</license-p></license></permissions></table-wrap><p>Autophagy is believed to be an ancient anti‐viral response. Upon evading the host, viral proteins can often be targeted by host autophagy pathway for lysosomal degradation, which promotes anti‐viral innate and adaptive immunities via facilitating viral protein processing and presentation to antigen‐presenting cells.<xref rid="cti21014-bib-0069" ref-type="ref">69</xref> It is recognised now that the autophagy pathway can play both anti‐viral and pro‐viral roles in the pathogenesis of different viruses. Some viruses can utilise autophagy proteins to foster their own growth intracellularly. Under such conditions, autophagy pathways are often served as scaffold for viral entry or served as inter‐cellular organelle to foster viral replication, suppressing innate immunity through insufficient viral protein presentation and preventing cell death.<xref rid="cti21014-bib-0070" ref-type="ref">70</xref> The immune system has developed alternative ways to interrupt viral protein synthesis. These include upregulation of inflammatory cytokines, such as interferons, to reinforce cellular stress and autophagy response to combat viruses.</p></sec><sec id="cti21014-sec-0015"><title>Evolution of cytokine‐driven interruption in protein biosynthesis</title><p>Our discovery of cytokine‐induced oxidative stress (ROS/NOS) within target cells provides a mechanism that bypasses this viral‐driven mechanism that block arms of the UPR. Innate cytokines are released quickly and dynamically. We identified selected cytokines that have a direct downstream chemical effect within the ER, which induces misfolding of viral proteins regardless of any viral blocking of the UPR (Figure <xref rid="cti21014-fig-0005" ref-type="fig">5</xref>). Translated viral proteins will misfold due to the inappropriate oxidative state in the ER, leading to host cell apoptosis and reduced virulence.</p><fig fig-type="Figure" xml:lang="en" id="cti21014-fig-0005" orientation="portrait" position="float"><label>Figure 5</label><caption><p>Proposed mechanism of anti‐viral function of cytokines. <italic>Pre‐infection</italic>: Basal level of <styled-content style="fixed-case" toggle="no">UPR</styled-content> maintains the homeostasis of secretory cell function. <italic>Infection:</italic> Host <styled-content style="fixed-case" toggle="no">ER</styled-content> stress and <styled-content style="fixed-case" toggle="no">UPR</styled-content> are intrinsic mechanisms that will limit viral protein synthesis. However, viruses can potentially bypass these mechanisms to replicate. Specific cytokines (such as type I <styled-content style="fixed-case" toggle="no">IFN</styled-content>s) that induce oxidative stress would lead to protein misfolding which will be beneficial in limiting viral infection. <italic>Post‐infection:</italic> Following viral clearance, the wound healing pathways are activated. Specific cytokines, such as <styled-content style="fixed-case" toggle="no">IL</styled-content>‐10, known to suppress <styled-content style="fixed-case" toggle="no">UPR</styled-content> signals and <styled-content style="fixed-case" toggle="no">ER</styled-content> stress, will allow the restoration of normal protein production in the cells.</p></caption><graphic id="nlm-graphic-11" xlink:href="CTI2-7-e1014-g005"></graphic></fig><p>The impact of cytokines on oxidative stress and the UPR can dictate protein biosynthesis. For example, type I interferon signalling has been shown to regulate chronic hepatitis B virus infection via induction of oxidative stress in epithelial cells.<xref rid="cti21014-bib-0071" ref-type="ref">71</xref>, <xref rid="cti21014-bib-0072" ref-type="ref">72</xref>, <xref rid="cti21014-bib-0073" ref-type="ref">73</xref>, <xref rid="cti21014-bib-0074" ref-type="ref">74</xref> Anti‐viral effects of other cytokines such as TNF‐α have also been shown to induce apoptotic pathways in infected cells. Our work shows that specific cytokines (IL‐17, IL‐23) locally cause ER stress, particularly in cells with an inherent susceptibility to protein misfolding or inadequate UPR.</p><p>As discussed, cytokines such as IL‐4, IL‐13 and IL‐10 can boost protein production in mucin‐secreting goblet cells.<xref rid="cti21014-bib-0054" ref-type="ref">54</xref>, <xref rid="cti21014-bib-0075" ref-type="ref">75</xref>, <xref rid="cti21014-bib-0076" ref-type="ref">76</xref> There are several reports of correlations of cytokine levels with disease; however, limited research has been done on the direct effect of cytokines on protein biosynthesis.</p></sec><sec id="cti21014-sec-0016"><title>Inappropriate activation of cytokine‐induced ER stress in chronic inflammation</title><p>While cytokines that amplify stress may be favorable in the context of halting viral replication, inappropriate or continued activation of this pathway in the absence of overt pathogens in chronic inflammatory diseases perpetuates a cycle of stress and inflammation.<xref rid="cti21014-bib-0077" ref-type="ref">77</xref> This could result in poor barrier function, due to reduced secretion of barrier proteins and diminished epithelial integrity (Figure <xref rid="cti21014-fig-0005" ref-type="fig">5</xref>). For example, type I IFNs are essential for clearing viral infection. However, prolonged activation of type I IFNs in chronic infection leads to immune dysfunction and exacerbated tissue damage in the respiratory tract.<xref rid="cti21014-bib-0077" ref-type="ref">77</xref>, <xref rid="cti21014-bib-0078" ref-type="ref">78</xref> A careful balance is required; inducing ER stress and UPR pathways will limit viral replication and promote viral clearance in acute infection. However, prolonged ER stress and UPR activation is detrimental to mucosal barrier regeneration and renewed homeostasis.</p><p>IL‐10 is an example of the multifaceted role a single cytokine can have on viral infection and the UPR. IL‐10 suppresses B‐cell antibody responses and T‐cell immunity; thus, its neutralisation leads to viral clearance.<xref rid="cti21014-bib-0079" ref-type="ref">79</xref> Human cytomegalovirus has been found to encode a decoy IL‐10‐like cytokine, which signals through the human IL‐10 receptor to circumvent detection and destruction by the host immune system.<xref rid="cti21014-bib-0080" ref-type="ref">80</xref> We have demonstrated that IL‐10 suppresses the UPR in secretory goblet cells in the intestine,<xref rid="cti21014-bib-0054" ref-type="ref">54</xref> allowing for increased protein production. Therefore, along with IL‐10‐mediated immunosuppressive effects on the immune cells, IL‐10‐induced protein production (via the regulation of the UPR) would allow for increased viral replication in these highly productive secretory cells. Despite the negative effects of IL‐10 in acute viral infection, the importance of IL‐10 in attenuating chronic inflammation is unequivocal.<xref rid="cti21014-bib-0081" ref-type="ref">81</xref>, <xref rid="cti21014-bib-0082" ref-type="ref">82</xref> Regardless, these cytokines controlling secretory protein synthesis in non‐immune cells are an overlooked paradigm in immunity. More detailed understanding will help identify novel targets that can be modulated in acute infection and more broadly in chronic inflammatory diseases to alleviate tissue damage.</p></sec></sec><sec id="cti21014-sec-0017"><title>Implications for therapy against viral replication and chronic pathology</title><p>Endemic and emerging viral infections cause profound morbidity and mortality, with over 13 500 hospitalisations and more than 3000 deaths per year in Australia due to influenza alone.<xref rid="cti21014-bib-0083" ref-type="ref">83</xref> Pathology in susceptible individuals is likely to involve either an inability to control the viral replication and dissemination, or the development of a local ‘cytokine storm’ damaging the mucosal epithelium. Better understanding of the contribution of ER stress‐associated UPR response in viral infection process, temporal sequence of events and pathways to initiation of chronic inflammation and tissue damage is imperative. Understanding how immune responses and inflammatory cytokines regulate UPR in viral infection is crucial, because boosting this physiological process via cytokines could open the way to novel approaches to limit viral replication and acute disease, and rescue individuals with persistent inflammation and associated tissue damage. Clearly, the UPR is intimately involved in viral replication: manipulating ER stress and UPR signalling could potentially limit viral replication and attenuate acute viral infections. Reduction in epithelial cell UPR activation in chronic disease provides an opportunity to limit persistent mucosal inflammation and the extent of tissue damage. The timing and nature of the cytokine response dictate time taken for both viral clearance and restoration of mucosal integrity and homeostasis. Manipulation of cytokine‐induced epithelial cell ER stress gives us a chance to tip this fine balance in favor of health rather than disease.</p></sec><sec sec-type="COI-statement" id="cti21014-sec-0019"><title>Conflict of interest</title><p>The authors declare that there is no conflict of interest associated with this manuscript.</p></sec></body><back><ack id="cti21014-sec-0018"><title>Acknowledgments</title><p>We acknowledge the funding support to the authors by Mater Foundation. Dr Hasnain is supported by University of Queensland Postdoctoral Fellowship (2014‐2017) and a NHMRC Career Development Fellowship (2018‐2021). Dr Wang is supported by the Foundation of Research Excellence Grant (awarded to Dr Hasnain). Mr Moniruzzaman is supported by Research Training Program Scholarship (Australian Government Department of Education and Training), University of Queensland Centennial Scholarship (University of Queensland) and Frank Clair Scholarship (Mater Research). We also acknowledge the technical support from University of Queensland Biological Resource Facility at Mater Medical Research Institute. 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