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Control of anterior GRadient 2 (AGR2) dimerization links endoplasmic reticulum proteostasis to inflammation

Identifieur interne : 000575 ( Ncbi/Merge ); précédent : 000574; suivant : 000576

Control of anterior GRadient 2 (AGR2) dimerization links endoplasmic reticulum proteostasis to inflammation

Auteurs : Marion Maurel ; Joanna Obacz ; Tony Avril ; Yong-Ping Ding ; Olga Papadodima ; Xavier Treton ; Fanny Daniel ; Eleftherios Pilalis ; Johanna Hörberg ; Wenyang Hou ; Marie-Claude Beauchamp ; Julien Tourneur-Marsille ; Dominique Cazals-Hatem ; Lucia Sommerova ; Afshin Samali ; Jan Tavernier ; Roman Hrstka ; Aurélien Dupont ; Delphine Fessart ; Frédéric Delom ; Martin E. Fernandez-Zapico ; Gregor Jansen ; Leif A. Eriksson ; David Y. Thomas ; Loydie Jerome-Majewska ; Ted Hupp ; Aristotelis Chatziioannou ; Eric Chevet ; Eric Ogier-Denis

Source :

RBID : PMC:6554669

Abstract

Abstract

Anterior gradient 2 (AGR2) is a dimeric protein disulfide isomerase family member involved in the regulation of protein quality control in the endoplasmic reticulum (ER). Mouse AGR2 deletion increases intestinal inflammation and promotes the development of inflammatory bowel disease (IBD). Although these biological effects are well established, the underlying molecular mechanisms of AGR2 function toward inflammation remain poorly defined. Here, using a protein–protein interaction screen to identify cellular regulators of AGR2 dimerization, we unveiled specific enhancers, including TMED2, and inhibitors of AGR2 dimerization, that control AGR2 functions. We demonstrate that modulation of AGR2 dimer formation, whether enhancing or inhibiting the process, yields pro‐inflammatory phenotypes, through either autophagy‐dependent processes or secretion of AGR2, respectively. We also demonstrate that in IBD and specifically in Crohn's disease, the levels of AGR2 dimerization modulators are selectively deregulated, and this correlates with severity of disease. Our study demonstrates that AGR2 dimers act as sensors of ER homeostasis which are disrupted upon ER stress and promote the secretion of AGR2 monomers. The latter might represent systemic alarm signals for pro‐inflammatory responses.


Url:
DOI: 10.15252/emmm.201810120
PubMed: 31040128
PubMed Central: 6554669

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PMC:6554669

Le document en format XML

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adient 2 (
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2) dimerization links endoplasmic reticulum proteostasis to inflammation</title>
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<name sortKey="Hrstka, Roman" sort="Hrstka, Roman" uniqKey="Hrstka R" first="Roman" last="Hrstka">Roman Hrstka</name>
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<name sortKey="Dupont, Aurelien" sort="Dupont, Aurelien" uniqKey="Dupont A" first="Aurélien" last="Dupont">Aurélien Dupont</name>
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<name sortKey="Fessart, Delphine" sort="Fessart, Delphine" uniqKey="Fessart D" first="Delphine" last="Fessart">Delphine Fessart</name>
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<name sortKey="Fernandez Apico, Martin E" sort="Fernandez Apico, Martin E" uniqKey="Fernandez Apico M" first="Martin E" last="Fernandez-Zapico">Martin E. Fernandez-Zapico</name>
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<name sortKey="Jansen, Gregor" sort="Jansen, Gregor" uniqKey="Jansen G" first="Gregor" last="Jansen">Gregor Jansen</name>
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<name sortKey="Eriksson, Leif A" sort="Eriksson, Leif A" uniqKey="Eriksson L" first="Leif A" last="Eriksson">Leif A. Eriksson</name>
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<name sortKey="Thomas, David Y" sort="Thomas, David Y" uniqKey="Thomas D" first="David Y" last="Thomas">David Y. Thomas</name>
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<name sortKey="Jerome Ajewska, Loydie" sort="Jerome Ajewska, Loydie" uniqKey="Jerome Ajewska L" first="Loydie" last="Jerome-Majewska">Loydie Jerome-Majewska</name>
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<name sortKey="Hupp, Ted" sort="Hupp, Ted" uniqKey="Hupp T" first="Ted" last="Hupp">Ted Hupp</name>
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<nlm:aff id="emmm201810120-aff-0008"></nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="emmm201810120-aff-0018"></nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Chevet, Eric" sort="Chevet, Eric" uniqKey="Chevet E" first="Eric" last="Chevet">Eric Chevet</name>
<affiliation>
<nlm:aff id="emmm201810120-aff-0001"></nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="emmm201810120-aff-0002"></nlm:aff>
</affiliation>
</author>
<author>
<name sortKey="Ogier Enis, Eric" sort="Ogier Enis, Eric" uniqKey="Ogier Enis E" first="Eric" last="Ogier-Denis">Eric Ogier-Denis</name>
<affiliation>
<nlm:aff id="emmm201810120-aff-0005"></nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="emmm201810120-aff-0006"></nlm:aff>
</affiliation>
<affiliation>
<nlm:aff id="emmm201810120-aff-0007"></nlm:aff>
</affiliation>
</author>
</analytic>
<series>
<title level="j">EMBO Molecular Medicine</title>
<idno type="ISSN">1757-4676</idno>
<idno type="eISSN">1757-4684</idno>
<imprint>
<date when="2019">2019</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc>
<textClass></textClass>
</profileDesc>
</teiHeader>
<front>
<div type="abstract" xml:lang="en">
<title>Abstract</title>
<p>Anterior gradient 2 (
<styled-content style="fixed-case">AGR</styled-content>
2) is a dimeric protein disulfide isomerase family member involved in the regulation of protein quality control in the endoplasmic reticulum (
<styled-content style="fixed-case">ER</styled-content>
). Mouse
<styled-content style="fixed-case">AGR</styled-content>
2 deletion increases intestinal inflammation and promotes the development of inflammatory bowel disease (
<styled-content style="fixed-case">IBD</styled-content>
). Although these biological effects are well established, the underlying molecular mechanisms of
<styled-content style="fixed-case">AGR</styled-content>
2 function toward inflammation remain poorly defined. Here, using a protein–protein interaction screen to identify cellular regulators of
<styled-content style="fixed-case">AGR</styled-content>
2 dimerization, we unveiled specific enhancers, including
<styled-content style="fixed-case">TMED</styled-content>
2, and inhibitors of
<styled-content style="fixed-case">AGR</styled-content>
2 dimerization, that control
<styled-content style="fixed-case">AGR</styled-content>
2 functions. We demonstrate that modulation of
<styled-content style="fixed-case">AGR</styled-content>
2 dimer formation, whether enhancing or inhibiting the process, yields pro‐inflammatory phenotypes, through either autophagy‐dependent processes or secretion of
<styled-content style="fixed-case">AGR</styled-content>
2, respectively. We also demonstrate that in
<styled-content style="fixed-case">IBD</styled-content>
and specifically in Crohn's disease, the levels of
<styled-content style="fixed-case">AGR</styled-content>
2 dimerization modulators are selectively deregulated, and this correlates with severity of disease. Our study demonstrates that
<styled-content style="fixed-case">AGR</styled-content>
2 dimers act as sensors of
<styled-content style="fixed-case">ER</styled-content>
homeostasis which are disrupted upon
<styled-content style="fixed-case">ER</styled-content>
stress and promote the secretion of
<styled-content style="fixed-case">AGR</styled-content>
2 monomers. The latter might represent systemic alarm signals for pro‐inflammatory responses.</p>
</div>
</front>
<back>
<div1 type="bibliography">
<listBibl>
<biblStruct></biblStruct>
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</listBibl>
</div1>
</back>
</TEI>
<pmc article-type="research-article">
<pmc-dir>properties open_access</pmc-dir>
<front>
<journal-meta>
<journal-id journal-id-type="nlm-ta">EMBO Mol Med</journal-id>
<journal-id journal-id-type="iso-abbrev">EMBO Mol Med</journal-id>
<journal-id journal-id-type="doi">10.1002/(ISSN)1757-4684</journal-id>
<journal-id journal-id-type="publisher-id">EMMM</journal-id>
<journal-id journal-id-type="hwp">embomm</journal-id>
<journal-title-group>
<journal-title>EMBO Molecular Medicine</journal-title>
</journal-title-group>
<issn pub-type="ppub">1757-4676</issn>
<issn pub-type="epub">1757-4684</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">31040128</article-id>
<article-id pub-id-type="pmc">6554669</article-id>
<article-id pub-id-type="doi">10.15252/emmm.201810120</article-id>
<article-id pub-id-type="publisher-id">EMMM201810120</article-id>
<article-categories>
<subj-group subj-group-type="overline">
<subject>Research Article</subject>
</subj-group>
<subj-group subj-group-type="heading">
<subject>Research Articles</subject>
</subj-group>
</article-categories>
<title-group>
<article-title>Control of anterior
<styled-content style="fixed-case">GR</styled-content>
adient 2 (
<styled-content style="fixed-case">AGR</styled-content>
2) dimerization links endoplasmic reticulum proteostasis to inflammation</article-title>
<alt-title alt-title-type="left-running-head">Marion Maurel
<italic>et al</italic>
</alt-title>
</title-group>
<contrib-group>
<contrib id="emmm201810120-cr-0001" contrib-type="author">
<name>
<surname>Maurel</surname>
<given-names>Marion</given-names>
</name>
<xref ref-type="aff" rid="emmm201810120-aff-0001">
<sup>1</sup>
</xref>
<xref ref-type="aff" rid="emmm201810120-aff-0002">
<sup>2</sup>
</xref>
<xref ref-type="aff" rid="emmm201810120-aff-0003">
<sup>3</sup>
</xref>
<xref ref-type="aff" rid="emmm201810120-aff-0004">
<sup>4</sup>
</xref>
<xref ref-type="author-notes" rid="emmm201810120-note-1001">
<sup></sup>
</xref>
</contrib>
<contrib id="emmm201810120-cr-0002" contrib-type="author">
<name>
<surname>Obacz</surname>
<given-names>Joanna</given-names>
</name>
<xref ref-type="aff" rid="emmm201810120-aff-0001">
<sup>1</sup>
</xref>
<xref ref-type="aff" rid="emmm201810120-aff-0002">
<sup>2</sup>
</xref>
<xref ref-type="author-notes" rid="emmm201810120-note-1001">
<sup></sup>
</xref>
</contrib>
<contrib id="emmm201810120-cr-0003" contrib-type="author">
<name>
<surname>Avril</surname>
<given-names>Tony</given-names>
</name>
<xref ref-type="aff" rid="emmm201810120-aff-0001">
<sup>1</sup>
</xref>
<xref ref-type="aff" rid="emmm201810120-aff-0002">
<sup>2</sup>
</xref>
<xref ref-type="author-notes" rid="emmm201810120-note-1001">
<sup></sup>
</xref>
</contrib>
<contrib id="emmm201810120-cr-0004" contrib-type="author">
<name>
<surname>Ding</surname>
<given-names>Yong‐Ping</given-names>
</name>
<xref ref-type="aff" rid="emmm201810120-aff-0005">
<sup>5</sup>
</xref>
<xref ref-type="aff" rid="emmm201810120-aff-0006">
<sup>6</sup>
</xref>
<xref ref-type="aff" rid="emmm201810120-aff-0007">
<sup>7</sup>
</xref>
</contrib>
<contrib id="emmm201810120-cr-0005" contrib-type="author">
<name>
<surname>Papadodima</surname>
<given-names>Olga</given-names>
</name>
<xref ref-type="aff" rid="emmm201810120-aff-0008">
<sup>8</sup>
</xref>
</contrib>
<contrib id="emmm201810120-cr-0006" contrib-type="author">
<name>
<surname>Treton</surname>
<given-names>Xavier</given-names>
</name>
<xref ref-type="aff" rid="emmm201810120-aff-0005">
<sup>5</sup>
</xref>
<xref ref-type="aff" rid="emmm201810120-aff-0006">
<sup>6</sup>
</xref>
<xref ref-type="aff" rid="emmm201810120-aff-0007">
<sup>7</sup>
</xref>
</contrib>
<contrib id="emmm201810120-cr-0007" contrib-type="author">
<name>
<surname>Daniel</surname>
<given-names>Fanny</given-names>
</name>
<xref ref-type="aff" rid="emmm201810120-aff-0005">
<sup>5</sup>
</xref>
<xref ref-type="aff" rid="emmm201810120-aff-0006">
<sup>6</sup>
</xref>
<xref ref-type="aff" rid="emmm201810120-aff-0007">
<sup>7</sup>
</xref>
</contrib>
<contrib id="emmm201810120-cr-0008" contrib-type="author">
<name>
<surname>Pilalis</surname>
<given-names>Eleftherios</given-names>
</name>
<xref ref-type="aff" rid="emmm201810120-aff-0008">
<sup>8</sup>
</xref>
<xref ref-type="aff" rid="emmm201810120-aff-0009">
<sup>9</sup>
</xref>
</contrib>
<contrib id="emmm201810120-cr-0009" contrib-type="author">
<name>
<surname>Hörberg</surname>
<given-names>Johanna</given-names>
</name>
<xref ref-type="aff" rid="emmm201810120-aff-0010">
<sup>10</sup>
</xref>
</contrib>
<contrib id="emmm201810120-cr-0010" contrib-type="author">
<name>
<surname>Hou</surname>
<given-names>Wenyang</given-names>
</name>
<xref ref-type="aff" rid="emmm201810120-aff-0011">
<sup>11</sup>
</xref>
</contrib>
<contrib id="emmm201810120-cr-0011" contrib-type="author">
<name>
<surname>Beauchamp</surname>
<given-names>Marie‐Claude</given-names>
</name>
<xref ref-type="aff" rid="emmm201810120-aff-0011">
<sup>11</sup>
</xref>
</contrib>
<contrib id="emmm201810120-cr-0012" contrib-type="author">
<name>
<surname>Tourneur‐Marsille</surname>
<given-names>Julien</given-names>
</name>
<xref ref-type="aff" rid="emmm201810120-aff-0005">
<sup>5</sup>
</xref>
<xref ref-type="aff" rid="emmm201810120-aff-0006">
<sup>6</sup>
</xref>
<xref ref-type="aff" rid="emmm201810120-aff-0007">
<sup>7</sup>
</xref>
</contrib>
<contrib id="emmm201810120-cr-0013" contrib-type="author">
<name>
<surname>Cazals‐Hatem</surname>
<given-names>Dominique</given-names>
</name>
<xref ref-type="aff" rid="emmm201810120-aff-0005">
<sup>5</sup>
</xref>
<xref ref-type="aff" rid="emmm201810120-aff-0006">
<sup>6</sup>
</xref>
<xref ref-type="aff" rid="emmm201810120-aff-0007">
<sup>7</sup>
</xref>
</contrib>
<contrib id="emmm201810120-cr-0014" contrib-type="author">
<name>
<surname>Sommerova</surname>
<given-names>Lucia</given-names>
</name>
<xref ref-type="aff" rid="emmm201810120-aff-0012">
<sup>12</sup>
</xref>
</contrib>
<contrib id="emmm201810120-cr-0015" contrib-type="author">
<name>
<surname>Samali</surname>
<given-names>Afshin</given-names>
</name>
<contrib-id contrib-id-type="orcid">https://orcid.org/0000-0002-8610-8375</contrib-id>
<xref ref-type="aff" rid="emmm201810120-aff-0004">
<sup>4</sup>
</xref>
</contrib>
<contrib id="emmm201810120-cr-0016" contrib-type="author">
<name>
<surname>Tavernier</surname>
<given-names>Jan</given-names>
</name>
<xref ref-type="aff" rid="emmm201810120-aff-0003">
<sup>3</sup>
</xref>
</contrib>
<contrib id="emmm201810120-cr-0017" contrib-type="author">
<name>
<surname>Hrstka</surname>
<given-names>Roman</given-names>
</name>
<xref ref-type="aff" rid="emmm201810120-aff-0012">
<sup>12</sup>
</xref>
</contrib>
<contrib id="emmm201810120-cr-0018" contrib-type="author">
<name>
<surname>Dupont</surname>
<given-names>Aurélien</given-names>
</name>
<xref ref-type="aff" rid="emmm201810120-aff-0013">
<sup>13</sup>
</xref>
</contrib>
<contrib id="emmm201810120-cr-0019" contrib-type="author">
<name>
<surname>Fessart</surname>
<given-names>Delphine</given-names>
</name>
<xref ref-type="aff" rid="emmm201810120-aff-0014">
<sup>14</sup>
</xref>
</contrib>
<contrib id="emmm201810120-cr-0020" contrib-type="author">
<name>
<surname>Delom</surname>
<given-names>Frédéric</given-names>
</name>
<xref ref-type="aff" rid="emmm201810120-aff-0014">
<sup>14</sup>
</xref>
</contrib>
<contrib id="emmm201810120-cr-0021" contrib-type="author">
<name>
<surname>Fernandez‐Zapico</surname>
<given-names>Martin E</given-names>
</name>
<xref ref-type="aff" rid="emmm201810120-aff-0015">
<sup>15</sup>
</xref>
</contrib>
<contrib id="emmm201810120-cr-0022" contrib-type="author">
<name>
<surname>Jansen</surname>
<given-names>Gregor</given-names>
</name>
<contrib-id contrib-id-type="orcid">https://orcid.org/0000-0002-0289-0022</contrib-id>
<xref ref-type="aff" rid="emmm201810120-aff-0016">
<sup>16</sup>
</xref>
</contrib>
<contrib id="emmm201810120-cr-0023" contrib-type="author">
<name>
<surname>Eriksson</surname>
<given-names>Leif A</given-names>
</name>
<xref ref-type="aff" rid="emmm201810120-aff-0010">
<sup>10</sup>
</xref>
</contrib>
<contrib id="emmm201810120-cr-0024" contrib-type="author">
<name>
<surname>Thomas</surname>
<given-names>David Y</given-names>
</name>
<xref ref-type="aff" rid="emmm201810120-aff-0016">
<sup>16</sup>
</xref>
</contrib>
<contrib id="emmm201810120-cr-0025" contrib-type="author">
<name>
<surname>Jerome‐Majewska</surname>
<given-names>Loydie</given-names>
</name>
<xref ref-type="aff" rid="emmm201810120-aff-0011">
<sup>11</sup>
</xref>
</contrib>
<contrib id="emmm201810120-cr-0026" contrib-type="author">
<name>
<surname>Hupp</surname>
<given-names>Ted</given-names>
</name>
<xref ref-type="aff" rid="emmm201810120-aff-0009">
<sup>9</sup>
</xref>
<xref ref-type="aff" rid="emmm201810120-aff-0012">
<sup>12</sup>
</xref>
<xref ref-type="aff" rid="emmm201810120-aff-0017">
<sup>17</sup>
</xref>
</contrib>
<contrib id="emmm201810120-cr-0027" contrib-type="author" corresp="yes">
<name>
<surname>Chatziioannou</surname>
<given-names>Aristotelis</given-names>
</name>
<contrib-id contrib-id-type="orcid">https://orcid.org/0000-0003-2078-0844</contrib-id>
<address>
<email>achatzi@eie.gr</email>
</address>
<xref ref-type="aff" rid="emmm201810120-aff-0008">
<sup>8</sup>
</xref>
<xref ref-type="aff" rid="emmm201810120-aff-0018">
<sup>18</sup>
</xref>
</contrib>
<contrib id="emmm201810120-cr-0028" contrib-type="author" corresp="yes">
<name>
<surname>Chevet</surname>
<given-names>Eric</given-names>
</name>
<contrib-id contrib-id-type="orcid">https://orcid.org/0000-0001-5855-4522</contrib-id>
<address>
<email>eric.chevet@inserm.fr</email>
</address>
<xref ref-type="aff" rid="emmm201810120-aff-0001">
<sup>1</sup>
</xref>
<xref ref-type="aff" rid="emmm201810120-aff-0002">
<sup>2</sup>
</xref>
</contrib>
<contrib id="emmm201810120-cr-0029" contrib-type="author" corresp="yes">
<name>
<surname>Ogier‐Denis</surname>
<given-names>Eric</given-names>
</name>
<contrib-id contrib-id-type="orcid">https://orcid.org/0000-0002-0057-7593</contrib-id>
<address>
<email>eric.ogier-denis@inserm.fr</email>
</address>
<xref ref-type="aff" rid="emmm201810120-aff-0005">
<sup>5</sup>
</xref>
<xref ref-type="aff" rid="emmm201810120-aff-0006">
<sup>6</sup>
</xref>
<xref ref-type="aff" rid="emmm201810120-aff-0007">
<sup>7</sup>
</xref>
</contrib>
</contrib-group>
<aff id="emmm201810120-aff-0001">
<label>
<sup>1</sup>
</label>
<named-content content-type="organisation-division">INSERM U1242, “Chemistry, Oncogenesis Stress Signaling”</named-content>
<institution>University of Rennes</institution>
<named-content content-type="city">Rennes</named-content>
<country country="FR">France</country>
</aff>
<aff id="emmm201810120-aff-0002">
<label>
<sup>2</sup>
</label>
<institution>Centre de Lutte Contre le Cancer Eugène Marquis</institution>
<named-content content-type="city">Rennes</named-content>
<country country="FR">France</country>
</aff>
<aff id="emmm201810120-aff-0003">
<label>
<sup>3</sup>
</label>
<named-content content-type="organisation-division">VIB Department of Medical Protein Research</named-content>
<institution>UGent</institution>
<named-content content-type="city">Gent</named-content>
<country country="BE">Belgium</country>
</aff>
<aff id="emmm201810120-aff-0004">
<label>
<sup>4</sup>
</label>
<named-content content-type="organisation-division">Apoptosis Research Centre</named-content>
<named-content content-type="organisation-division">School of Natural Sciences</named-content>
<institution>NUI Galway</institution>
<named-content content-type="city">Galway</named-content>
<country country="IE">Ireland</country>
</aff>
<aff id="emmm201810120-aff-0005">
<label>
<sup>5</sup>
</label>
<named-content content-type="organisation-division">INSERM, UMR1149, Team «Gut Inflammation»</named-content>
<institution>Research Centre of Inflammation</institution>
<named-content content-type="city">Paris</named-content>
<country country="FR">France</country>
</aff>
<aff id="emmm201810120-aff-0006">
<label>
<sup>6</sup>
</label>
<institution>Université Paris‐Diderot Sorbonne Paris‐Cité</institution>
<named-content content-type="city">Paris</named-content>
<country country="FR">France</country>
</aff>
<aff id="emmm201810120-aff-0007">
<label>
<sup>7</sup>
</label>
<institution>APHP Beaujon Hospital Clichy la Garenne</institution>
<named-content content-type="city">Paris</named-content>
<country country="FR">France</country>
</aff>
<aff id="emmm201810120-aff-0008">
<label>
<sup>8</sup>
</label>
<named-content content-type="organisation-division">Institute of Biology, Medicinal Chemistry & Biotechnology</named-content>
<institution>NHRF</institution>
<named-content content-type="city">Athens</named-content>
<country country="GR">Greece</country>
</aff>
<aff id="emmm201810120-aff-0009">
<label>
<sup>9</sup>
</label>
<institution>International Centre for Cancer Vaccine Science</institution>
<named-content content-type="city">Gdansk</named-content>
<country country="PL">Poland</country>
</aff>
<aff id="emmm201810120-aff-0010">
<label>
<sup>10</sup>
</label>
<named-content content-type="organisation-division">Department of Chemistry and Molecular Biology</named-content>
<institution>University of Gothenburg</institution>
<named-content content-type="city">Göteborg</named-content>
<country country="SE">Sweden</country>
</aff>
<aff id="emmm201810120-aff-0011">
<label>
<sup>11</sup>
</label>
<named-content content-type="organisation-division">Departments of Anatomy and Cell Biology, Human Genetics, and Pediatrics</named-content>
<institution>McGill University</institution>
<named-content content-type="city">Montreal</named-content>
<named-content content-type="country-part">QC</named-content>
<country country="CA">Canada</country>
</aff>
<aff id="emmm201810120-aff-0012">
<label>
<sup>12</sup>
</label>
<institution>Regional Centre for Applied Molecular Oncology (RECAMO)</institution>
<named-content content-type="city">Brno</named-content>
<country country="CZ">Czech Republic</country>
</aff>
<aff id="emmm201810120-aff-0013">
<label>
<sup>13</sup>
</label>
<named-content content-type="organisation-division">Microscopy Rennes Imaging Centre, and Biosit</named-content>
<named-content content-type="organisation-division">UMS3480 CNRS</named-content>
<institution>University of Rennes 1</institution>
<named-content content-type="city">Rennes Cédex</named-content>
<country country="FR">France</country>
</aff>
<aff id="emmm201810120-aff-0014">
<label>
<sup>14</sup>
</label>
<institution>University of Bordeaux</institution>
<named-content content-type="city">Bordeaux</named-content>
<country country="FR">France</country>
</aff>
<aff id="emmm201810120-aff-0015">
<label>
<sup>15</sup>
</label>
<named-content content-type="organisation-division">Division of Oncology Research</named-content>
<named-content content-type="organisation-division">Department of Oncology</named-content>
<named-content content-type="organisation-division">Schulze Center for Novel Therapeutics</named-content>
<institution>Mayo Clinic</institution>
<named-content content-type="city">Rochester</named-content>
<named-content content-type="country-part">MN</named-content>
<country country="US">USA</country>
</aff>
<aff id="emmm201810120-aff-0016">
<label>
<sup>16</sup>
</label>
<named-content content-type="organisation-division">Biochemistry Department</named-content>
<institution>McGill University Life Sciences Complex</institution>
<named-content content-type="city">Montréal</named-content>
<named-content content-type="country-part">QC</named-content>
<country country="CA">Canada</country>
</aff>
<aff id="emmm201810120-aff-0017">
<label>
<sup>17</sup>
</label>
<named-content content-type="organisation-division">Edinburgh Cancer Research Centre at the Institute of Genetics and Molecular Medicine</named-content>
<institution>Edinburgh University</institution>
<named-content content-type="city">Edimburgh</named-content>
<country country="GB">UK</country>
</aff>
<aff id="emmm201810120-aff-0018">
<label>
<sup>18</sup>
</label>
<institution>e‐NIOS PC</institution>
<named-content content-type="city">Kallithea‐Athens</named-content>
<country country="GR">Greece</country>
</aff>
<author-notes>
<corresp id="correspondenceTo">
<label>*</label>
Corresponding author. Tel: +30 2107273751; E‐mail:
<email>achatzi@eie.gr</email>
<break></break>
Corresponding author. Tel: +33 223237258; E‐mail:
<email>eric.chevet@inserm.fr</email>
<break></break>
Corresponding author. Tel: +33 157277307; E‐mail:
<email>eric.ogier-denis@inserm.fr</email>
<break></break>
</corresp>
<fn fn-type="equal" id="emmm201810120-note-1001">
<label></label>
<p>These authors contributed equally to this work</p>
</fn>
</author-notes>
<pub-date pub-type="epub">
<day>30</day>
<month>4</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="ppub">
<month>6</month>
<year>2019</year>
</pub-date>
<volume>11</volume>
<issue>6</issue>
<issue-id pub-id-type="doi">10.1002/emmm.v11.6</issue-id>
<elocation-id>e10120</elocation-id>
<history>
<date date-type="received">
<day>23</day>
<month>11</month>
<year>2018</year>
</date>
<date date-type="rev-recd">
<day>28</day>
<month>3</month>
<year>2019</year>
</date>
<date date-type="accepted">
<day>07</day>
<month>4</month>
<year>2019</year>
</date>
</history>
<permissions>
<pmc-comment> © 2019 EMBO </pmc-comment>
<copyright-statement content-type="article-copyright">© 2019 The Authors. Published under the terms of the CC BY 4.0 license</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:type="simple" xlink:href="file:EMMM-11-e10120.pdf"></self-uri>
<abstract id="emmm201810120-abs-0001">
<title>Abstract</title>
<p>Anterior gradient 2 (
<styled-content style="fixed-case">AGR</styled-content>
2) is a dimeric protein disulfide isomerase family member involved in the regulation of protein quality control in the endoplasmic reticulum (
<styled-content style="fixed-case">ER</styled-content>
). Mouse
<styled-content style="fixed-case">AGR</styled-content>
2 deletion increases intestinal inflammation and promotes the development of inflammatory bowel disease (
<styled-content style="fixed-case">IBD</styled-content>
). Although these biological effects are well established, the underlying molecular mechanisms of
<styled-content style="fixed-case">AGR</styled-content>
2 function toward inflammation remain poorly defined. Here, using a protein–protein interaction screen to identify cellular regulators of
<styled-content style="fixed-case">AGR</styled-content>
2 dimerization, we unveiled specific enhancers, including
<styled-content style="fixed-case">TMED</styled-content>
2, and inhibitors of
<styled-content style="fixed-case">AGR</styled-content>
2 dimerization, that control
<styled-content style="fixed-case">AGR</styled-content>
2 functions. We demonstrate that modulation of
<styled-content style="fixed-case">AGR</styled-content>
2 dimer formation, whether enhancing or inhibiting the process, yields pro‐inflammatory phenotypes, through either autophagy‐dependent processes or secretion of
<styled-content style="fixed-case">AGR</styled-content>
2, respectively. We also demonstrate that in
<styled-content style="fixed-case">IBD</styled-content>
and specifically in Crohn's disease, the levels of
<styled-content style="fixed-case">AGR</styled-content>
2 dimerization modulators are selectively deregulated, and this correlates with severity of disease. Our study demonstrates that
<styled-content style="fixed-case">AGR</styled-content>
2 dimers act as sensors of
<styled-content style="fixed-case">ER</styled-content>
homeostasis which are disrupted upon
<styled-content style="fixed-case">ER</styled-content>
stress and promote the secretion of
<styled-content style="fixed-case">AGR</styled-content>
2 monomers. The latter might represent systemic alarm signals for pro‐inflammatory responses.</p>
</abstract>
<kwd-group kwd-group-type="author-generated">
<kwd id="emmm201810120-kwd-0001">
<styled-content style="fixed-case">AGR</styled-content>
2</kwd>
<kwd id="emmm201810120-kwd-0002">endoplasmic reticulum</kwd>
<kwd id="emmm201810120-kwd-0003">inflammation</kwd>
<kwd id="emmm201810120-kwd-0004">proteostasis</kwd>
<kwd id="emmm201810120-kwd-0005">
<styled-content style="fixed-case">TMED</styled-content>
2</kwd>
</kwd-group>
<kwd-group kwd-group-type="subject-categories">
<title>Subject Categories</title>
<kwd>Digestive System</kwd>
<kwd>Immunology</kwd>
<kwd>Metabolism</kwd>
</kwd-group>
<funding-group>
<award-group>
<funding-source>Fonds Wetenschappelijk Onderzoek (FWO)</funding-source>
</award-group>
<award-group>
<funding-source>Rennes Metropole</funding-source>
</award-group>
<award-group>
<funding-source>Priority Health of the Peripheral Entrepreneurial Program of Attiki</funding-source>
</award-group>
<award-group>
<funding-source>Gouvernement du Canada | Canadian Institutes of Health Research (CIHR)</funding-source>
</award-group>
<award-group>
<funding-source>GACR</funding-source>
<award-id>19‐02014S</award-id>
</award-group>
<award-group>
<funding-source>Institut National de la Santé et de la Recherche Médicale (Inserm)</funding-source>
</award-group>
<award-group>
<funding-source>Region Bretagne</funding-source>
</award-group>
<award-group>
<funding-source>Canceropole grand sud ouest</funding-source>
</award-group>
<award-group>
<funding-source>EC|H2020|H2020 Priority Excellent Science|H2020 Marie Skłodowska‐Curie Actions (MSCA)</funding-source>
<award-id>ITN‐675448</award-id>
<award-id>RISE‐734749</award-id>
</award-group>
<award-group>
<funding-source>Svenska Forskningsrådet Formas (Swedish Research Council Formas)</funding-source>
<award-id>2014‐3914</award-id>
</award-group>
<award-group>
<funding-source>Agence Nationale de la Recherche (ANR)</funding-source>
<award-id>ANR‐11‐IDEX‐0005‐02</award-id>
</award-group>
<award-group>
<funding-source>Institut National du Cancer</funding-source>
<award-id>PLBIO INCa_5869</award-id>
</award-group>
<award-group>
<funding-source>Swedish Research Council</funding-source>
<award-id>2014‐3914</award-id>
</award-group>
</funding-group>
<counts>
<fig-count count="7"></fig-count>
<table-count count="0"></table-count>
<page-count count="19"></page-count>
<word-count count="12519"></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>component-id</meta-name>
<meta-value>emmm201810120</meta-value>
</custom-meta>
<custom-meta>
<meta-name>cover-date</meta-name>
<meta-value>June 2019</meta-value>
</custom-meta>
<custom-meta>
<meta-name>details-of-publishers-convertor</meta-name>
<meta-value>Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.4 mode:remove_FC converted:07.06.2019</meta-value>
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</custom-meta-group>
</article-meta>
<notes>
<p content-type="self-citation">
<mixed-citation publication-type="journal" id="emmm201810120-cit-1001">
<source xml:lang="en">EMBO Mol Med</source>
(
<year>2019</year>
)
<volume>11</volume>
:
<elocation-id>e10120</elocation-id>
</mixed-citation>
</p>
</notes>
</front>
</pmc>
<affiliations>
<list></list>
<tree>
<noCountry>
<name sortKey="Avril, Tony" sort="Avril, Tony" uniqKey="Avril T" first="Tony" last="Avril">Tony Avril</name>
<name sortKey="Beauchamp, Marie Laude" sort="Beauchamp, Marie Laude" uniqKey="Beauchamp M" first="Marie-Claude" last="Beauchamp">Marie-Claude Beauchamp</name>
<name sortKey="Cazals Atem, Dominique" sort="Cazals Atem, Dominique" uniqKey="Cazals Atem D" first="Dominique" last="Cazals-Hatem">Dominique Cazals-Hatem</name>
<name sortKey="Chatziioannou, Aristotelis" sort="Chatziioannou, Aristotelis" uniqKey="Chatziioannou A" first="Aristotelis" last="Chatziioannou">Aristotelis Chatziioannou</name>
<name sortKey="Chevet, Eric" sort="Chevet, Eric" uniqKey="Chevet E" first="Eric" last="Chevet">Eric Chevet</name>
<name sortKey="Daniel, Fanny" sort="Daniel, Fanny" uniqKey="Daniel F" first="Fanny" last="Daniel">Fanny Daniel</name>
<name sortKey="Delom, Frederic" sort="Delom, Frederic" uniqKey="Delom F" first="Frédéric" last="Delom">Frédéric Delom</name>
<name sortKey="Ding, Yong Ing" sort="Ding, Yong Ing" uniqKey="Ding Y" first="Yong-Ping" last="Ding">Yong-Ping Ding</name>
<name sortKey="Dupont, Aurelien" sort="Dupont, Aurelien" uniqKey="Dupont A" first="Aurélien" last="Dupont">Aurélien Dupont</name>
<name sortKey="Eriksson, Leif A" sort="Eriksson, Leif A" uniqKey="Eriksson L" first="Leif A" last="Eriksson">Leif A. Eriksson</name>
<name sortKey="Fernandez Apico, Martin E" sort="Fernandez Apico, Martin E" uniqKey="Fernandez Apico M" first="Martin E" last="Fernandez-Zapico">Martin E. Fernandez-Zapico</name>
<name sortKey="Fessart, Delphine" sort="Fessart, Delphine" uniqKey="Fessart D" first="Delphine" last="Fessart">Delphine Fessart</name>
<name sortKey="Horberg, Johanna" sort="Horberg, Johanna" uniqKey="Horberg J" first="Johanna" last="Hörberg">Johanna Hörberg</name>
<name sortKey="Hou, Wenyang" sort="Hou, Wenyang" uniqKey="Hou W" first="Wenyang" last="Hou">Wenyang Hou</name>
<name sortKey="Hrstka, Roman" sort="Hrstka, Roman" uniqKey="Hrstka R" first="Roman" last="Hrstka">Roman Hrstka</name>
<name sortKey="Hupp, Ted" sort="Hupp, Ted" uniqKey="Hupp T" first="Ted" last="Hupp">Ted Hupp</name>
<name sortKey="Jansen, Gregor" sort="Jansen, Gregor" uniqKey="Jansen G" first="Gregor" last="Jansen">Gregor Jansen</name>
<name sortKey="Jerome Ajewska, Loydie" sort="Jerome Ajewska, Loydie" uniqKey="Jerome Ajewska L" first="Loydie" last="Jerome-Majewska">Loydie Jerome-Majewska</name>
<name sortKey="Maurel, Marion" sort="Maurel, Marion" uniqKey="Maurel M" first="Marion" last="Maurel">Marion Maurel</name>
<name sortKey="Obacz, Joanna" sort="Obacz, Joanna" uniqKey="Obacz J" first="Joanna" last="Obacz">Joanna Obacz</name>
<name sortKey="Ogier Enis, Eric" sort="Ogier Enis, Eric" uniqKey="Ogier Enis E" first="Eric" last="Ogier-Denis">Eric Ogier-Denis</name>
<name sortKey="Papadodima, Olga" sort="Papadodima, Olga" uniqKey="Papadodima O" first="Olga" last="Papadodima">Olga Papadodima</name>
<name sortKey="Pilalis, Eleftherios" sort="Pilalis, Eleftherios" uniqKey="Pilalis E" first="Eleftherios" last="Pilalis">Eleftherios Pilalis</name>
<name sortKey="Samali, Afshin" sort="Samali, Afshin" uniqKey="Samali A" first="Afshin" last="Samali">Afshin Samali</name>
<name sortKey="Sommerova, Lucia" sort="Sommerova, Lucia" uniqKey="Sommerova L" first="Lucia" last="Sommerova">Lucia Sommerova</name>
<name sortKey="Tavernier, Jan" sort="Tavernier, Jan" uniqKey="Tavernier J" first="Jan" last="Tavernier">Jan Tavernier</name>
<name sortKey="Thomas, David Y" sort="Thomas, David Y" uniqKey="Thomas D" first="David Y" last="Thomas">David Y. Thomas</name>
<name sortKey="Tourneur Arsille, Julien" sort="Tourneur Arsille, Julien" uniqKey="Tourneur Arsille J" first="Julien" last="Tourneur-Marsille">Julien Tourneur-Marsille</name>
<name sortKey="Treton, Xavier" sort="Treton, Xavier" uniqKey="Treton X" first="Xavier" last="Treton">Xavier Treton</name>
</noCountry>
</tree>
</affiliations>
</record>

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