CRBN Is a Negative Regulator of Bactericidal Activity and Autophagy Activation Through Inhibiting the Ubiquitination of ECSIT and BECN1
Identifieur interne : 000542 ( Pmc/Curation ); précédent : 000541; suivant : 000543CRBN Is a Negative Regulator of Bactericidal Activity and Autophagy Activation Through Inhibiting the Ubiquitination of ECSIT and BECN1
Auteurs : Mi-Jeong Kim [Corée du Sud] ; Yoon Min [Corée du Sud] ; Jae-Hyuck Shim [États-Unis] ; Eunyoung Chun [États-Unis] ; Ki-Young Lee [Corée du Sud]Source :
- Frontiers in Immunology [ 1664-3224 ] ; 2019.
Abstract
Cereblon (CRBN) as a multifunctional protein has been extensively studied. Here, we show that CRBN is a negative regulator of bactericidal activity and autophagy activation. Mitochondrial localization of CRBN was significantly increased in response to Toll-like receptor 4 (TLR4) stimulation. CRBN interrupted the association of evolutionarily conserved signaling intermediate in Toll pathways (ECSIT)-TNF-receptor associated factor 6 (TRAF6) complex, thereby inhibiting the ubiquitination of ECSIT, which plays a pivotal role for the production of mitochondrial reactive oxygen species (mROS). Subsequently, mROS levels were markedly elevated in CRBN-knockdown (CRBNKD) THP-1 cells, and that led to resistance against S. typhimurium infection, indicating CRBN is a negative regulator of bactericidal activity through the regulation of mROS. Additionally, CRBN inhibited TRAF6-induced ubiquitination of BECN1 (Beclin 1), and that induced autophagy activation in CRBNKD THP-1, CRBN-knockout (CRBNKO) H1299, and CRBNKO MCF7 cancer cells in response to TLR4 stimulation. Notably, we found that the ability of cancer migration and invasion was significantly enhanced in CRBNKO H1299 and CRBNKO MCF7 cancer cells, as compared with those of control cancer cells. Collectively, these results suggest that CRBN is a negative regulator of bactericidal activity and autophagy activation through inhibiting the TRAF6-induced ubiquitination of ECSIT and BECN1, respectively.
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DOI: 10.3389/fimmu.2019.02203
PubMed: 31620128
PubMed Central: 6759600
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University School of Medicine</institution>,<addr-line>Suwon</addr-line>,<country>South Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Shim, Jae Hyuck" sort="Shim, Jae Hyuck" uniqKey="Shim J" first="Jae-Hyuck" last="Shim">Jae-Hyuck Shim</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School</institution>,<addr-line>Worcester, MA</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Chun, Eunyoung" sort="Chun, Eunyoung" uniqKey="Chun E" first="Eunyoung" last="Chun">Eunyoung Chun</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Department of Immunology and Infectious Diseases, Harvard 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Min</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Molecular Cell Biology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine</institution>,<addr-line>Suwon</addr-line>,<country>South Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Shim, Jae Hyuck" sort="Shim, Jae Hyuck" uniqKey="Shim J" first="Jae-Hyuck" last="Shim">Jae-Hyuck Shim</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School</institution>,<addr-line>Worcester, MA</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Chun, Eunyoung" sort="Chun, Eunyoung" uniqKey="Chun E" first="Eunyoung" last="Chun">Eunyoung Chun</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Department of Immunology and Infectious Diseases, Harvard School of Public Health</institution>,<addr-line>Boston, MA</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Department of Medicine, Harvard Medical School</institution>,<addr-line>Boston, MA</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Lee, Ki Young" sort="Lee, Ki Young" uniqKey="Lee K" first="Ki-Young" last="Lee">Ki-Young Lee</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Molecular Cell Biology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine</institution>,<addr-line>Suwon</addr-line>,<country>South Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff5"><institution>Department of Health Sciences and Technology, Samsung Medical Center, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University</institution>,<addr-line>Seoul</addr-line>,<country>South Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Frontiers in Immunology</title><idno type="eISSN">1664-3224</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Cereblon (CRBN) as a multifunctional protein has been extensively studied. Here, we show that CRBN is a negative regulator of bactericidal activity and autophagy activation. Mitochondrial localization of CRBN was significantly increased in response to Toll-like receptor 4 (TLR4) stimulation. CRBN interrupted the association of evolutionarily conserved signaling intermediate in Toll pathways (ECSIT)-TNF-receptor associated factor 6 (TRAF6) complex, thereby inhibiting the ubiquitination of ECSIT, which plays a pivotal role for the production of mitochondrial reactive oxygen species (mROS). Subsequently, mROS levels were markedly elevated in CRBN-knockdown (CRBN<sup>KD</sup>) THP-1 cells, and that led to resistance against S. typhimurium infection, indicating CRBN is a negative regulator of bactericidal activity through the regulation of mROS. Additionally, CRBN inhibited TRAF6-induced ubiquitination of BECN1 (Beclin 1), and that induced autophagy activation in CRBN<sup>KD</sup> THP-1, CRBN-knockout (CRBN<sup>KO</sup>) H1299, and CRBN<sup>KO</sup> MCF7 cancer cells in response to TLR4 stimulation. Notably, we found that the ability of cancer migration and invasion was significantly enhanced in CRBN<sup>KO</sup> H1299 and CRBN<sup>KO</sup> MCF7 cancer cells, as compared with those of control cancer cells. Collectively, these results suggest that CRBN is a negative regulator of bactericidal activity and autophagy activation through inhibiting the TRAF6-induced ubiquitination of ECSIT and BECN1, respectively.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Higgins, Jj" uniqKey="Higgins J">JJ Higgins</name></author><author><name sortKey="Pucilowska, J" uniqKey="Pucilowska J">J Pucilowska</name></author><author><name sortKey="Lombardi, Rq" uniqKey="Lombardi R">RQ Lombardi</name></author><author><name sortKey="Rooney, Jp" uniqKey="Rooney J">JP Rooney</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Basel Vanagaite, L" uniqKey="Basel Vanagaite L">L Basel-Vanagaite</name></author><author><name sortKey="Attia, R" uniqKey="Attia R">R Attia</name></author><author><name sortKey="Yahav, M" uniqKey="Yahav M">M Yahav</name></author><author><name sortKey="Ferland, Rj" uniqKey="Ferland R">RJ 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Front Immunol</journal-id><journal-id journal-id-type="iso-abbrev">Front Immunol</journal-id><journal-id journal-id-type="publisher-id">Front. Immunol.</journal-id><journal-title-group><journal-title>Frontiers in Immunology</journal-title></journal-title-group><issn pub-type="epub">1664-3224</issn><publisher><publisher-name>Frontiers Media S.A.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31620128</article-id><article-id pub-id-type="pmc">6759600</article-id><article-id pub-id-type="doi">10.3389/fimmu.2019.02203</article-id><article-categories><subj-group subj-group-type="heading"><subject>Immunology</subject><subj-group><subject>Original Research</subject></subj-group></subj-group></article-categories><title-group><article-title>CRBN Is a Negative Regulator of Bactericidal Activity and Autophagy Activation Through Inhibiting the Ubiquitination of ECSIT and BECN1</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Kim</surname><given-names>Mi-Jeong</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="author-notes" rid="fn002"><sup>†</sup></xref></contrib><contrib contrib-type="author"><name><surname>Min</surname><given-names>Yoon</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="author-notes" rid="fn002"><sup>†</sup></xref></contrib><contrib contrib-type="author"><name><surname>Shim</surname><given-names>Jae-Hyuck</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Chun</surname><given-names>Eunyoung</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><xref ref-type="aff" rid="aff4"><sup>4</sup></xref><xref ref-type="corresp" rid="c001"><sup>*</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lee</surname><given-names>Ki-Young</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff5"><sup>5</sup></xref><xref ref-type="corresp" rid="c002"><sup>*</sup></xref><uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/395669/overview"></uri></contrib></contrib-group><aff id="aff1"><sup>1</sup><institution>Department of Molecular Cell Biology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine</institution>,<addr-line>Suwon</addr-line>,<country>South Korea</country></aff><aff id="aff2"><sup>2</sup><institution>Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School</institution>,<addr-line>Worcester, MA</addr-line>,<country>United States</country></aff><aff id="aff3"><sup>3</sup><institution>Department of Immunology and Infectious Diseases, Harvard School of Public Health</institution>,<addr-line>Boston, MA</addr-line>,<country>United States</country></aff><aff id="aff4"><sup>4</sup><institution>Department of Medicine, Harvard Medical School</institution>,<addr-line>Boston, MA</addr-line>,<country>United States</country></aff><aff id="aff5"><sup>5</sup><institution>Department of Health Sciences and Technology, Samsung Medical Center, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University</institution>,<addr-line>Seoul</addr-line>,<country>South Korea</country></aff><author-notes><fn fn-type="edited-by"><p>Edited by: Amy Rasley, United States Department of Energy (DOE), United States</p></fn><fn fn-type="edited-by"><p>Reviewed by: Lilliana Radoshevich, University of Iowa, United States; Heung Kyu Lee, Korea Advanced Institute of Science and Technology (KAIST), South Korea</p></fn><corresp id="c001">*Correspondence: Eunyoung Chun <email>echun@hsph.harvard.edu</email></corresp><corresp id="c002">Ki-Young Lee <email>thylee@skku.edu</email></corresp><fn fn-type="other" id="fn001"><p>This article was submitted to Microbial Immunology, a section of the journal Frontiers in Immunology</p></fn><fn fn-type="other" id="fn002"><p>†These authors have contributed equally to this work</p></fn></author-notes><pub-date pub-type="epub"><day>18</day><month>9</month><year>2019</year></pub-date><pub-date pub-type="collection"><year>2019</year></pub-date><volume>10</volume><elocation-id>2203</elocation-id><history><date date-type="received"><day>24</day><month>1</month><year>2019</year></date><date date-type="accepted"><day>30</day><month>8</month><year>2019</year></date></history><permissions><copyright-statement>Copyright © 2019 Kim, Min, Shim, Chun and Lee.</copyright-statement><copyright-year>2019</copyright-year><copyright-holder>Kim, Min, Shim, Chun and Lee</copyright-holder><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</license-p></license></permissions><abstract><p>Cereblon (CRBN) as a multifunctional protein has been extensively studied. Here, we show that CRBN is a negative regulator of bactericidal activity and autophagy activation. Mitochondrial localization of CRBN was significantly increased in response to Toll-like receptor 4 (TLR4) stimulation. CRBN interrupted the association of evolutionarily conserved signaling intermediate in Toll pathways (ECSIT)-TNF-receptor associated factor 6 (TRAF6) complex, thereby inhibiting the ubiquitination of ECSIT, which plays a pivotal role for the production of mitochondrial reactive oxygen species (mROS). Subsequently, mROS levels were markedly elevated in CRBN-knockdown (CRBN<sup>KD</sup>) THP-1 cells, and that led to resistance against S. typhimurium infection, indicating CRBN is a negative regulator of bactericidal activity through the regulation of mROS. Additionally, CRBN inhibited TRAF6-induced ubiquitination of BECN1 (Beclin 1), and that induced autophagy activation in CRBN<sup>KD</sup> THP-1, CRBN-knockout (CRBN<sup>KO</sup>) H1299, and CRBN<sup>KO</sup> MCF7 cancer cells in response to TLR4 stimulation. Notably, we found that the ability of cancer migration and invasion was significantly enhanced in CRBN<sup>KO</sup> H1299 and CRBN<sup>KO</sup> MCF7 cancer cells, as compared with those of control cancer cells. Collectively, these results suggest that CRBN is a negative regulator of bactericidal activity and autophagy activation through inhibiting the TRAF6-induced ubiquitination of ECSIT and BECN1, respectively.</p></abstract><kwd-group><kwd>cereblon</kwd><kwd>toll-like receptor 4</kwd><kwd>TRAF6</kwd><kwd>ECSIT</kwd><kwd>BECN1</kwd><kwd>ubiquitination</kwd><kwd>mROS</kwd></kwd-group><counts><fig-count count="8"></fig-count><table-count count="0"></table-count><equation-count count="0"></equation-count><ref-count count="39"></ref-count><page-count count="14"></page-count><word-count count="8346"></word-count></counts></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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