Control of anterior GRadient 2 (AGR2) dimerization links endoplasmic reticulum proteostasis to inflammation
Identifieur interne : 000575 ( Ncbi/Merge ); précédent : 000574; suivant : 000576Control 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-DenisSource :
- EMBO Molecular Medicine [ 1757-4676 ] ; 2019.
Abstract
Anterior gradient 2 (
Url:
DOI: 10.15252/emmm.201810120
PubMed: 31040128
PubMed Central: 6554669
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PMC:6554669Le document en format XML
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adient 2 (<styled-content style="fixed-case">AGR</styled-content>
2) dimerization links endoplasmic reticulum proteostasis to inflammation</title>
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<author><name sortKey="Obacz, Joanna" sort="Obacz, Joanna" uniqKey="Obacz J" first="Joanna" last="Obacz">Joanna Obacz</name>
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<author><name sortKey="Avril, Tony" sort="Avril, Tony" uniqKey="Avril T" first="Tony" last="Avril">Tony Avril</name>
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<author><name sortKey="Ding, Yong Ing" sort="Ding, Yong Ing" uniqKey="Ding Y" first="Yong-Ping" last="Ding">Yong-Ping Ding</name>
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<author><name sortKey="Papadodima, Olga" sort="Papadodima, Olga" uniqKey="Papadodima O" first="Olga" last="Papadodima">Olga Papadodima</name>
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<author><name sortKey="Treton, Xavier" sort="Treton, Xavier" uniqKey="Treton X" first="Xavier" last="Treton">Xavier Treton</name>
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<author><name sortKey="Daniel, Fanny" sort="Daniel, Fanny" uniqKey="Daniel F" first="Fanny" last="Daniel">Fanny Daniel</name>
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<author><name sortKey="Pilalis, Eleftherios" sort="Pilalis, Eleftherios" uniqKey="Pilalis E" first="Eleftherios" last="Pilalis">Eleftherios Pilalis</name>
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<author><name sortKey="Horberg, Johanna" sort="Horberg, Johanna" uniqKey="Horberg J" first="Johanna" last="Hörberg">Johanna Hörberg</name>
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<author><name sortKey="Hou, Wenyang" sort="Hou, Wenyang" uniqKey="Hou W" first="Wenyang" last="Hou">Wenyang Hou</name>
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<author><name sortKey="Beauchamp, Marie Laude" sort="Beauchamp, Marie Laude" uniqKey="Beauchamp M" first="Marie-Claude" last="Beauchamp">Marie-Claude Beauchamp</name>
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<author><name sortKey="Tourneur Arsille, Julien" sort="Tourneur Arsille, Julien" uniqKey="Tourneur Arsille J" first="Julien" last="Tourneur-Marsille">Julien Tourneur-Marsille</name>
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<author><name sortKey="Cazals Atem, Dominique" sort="Cazals Atem, Dominique" uniqKey="Cazals Atem D" first="Dominique" last="Cazals-Hatem">Dominique Cazals-Hatem</name>
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<author><name sortKey="Sommerova, Lucia" sort="Sommerova, Lucia" uniqKey="Sommerova L" first="Lucia" last="Sommerova">Lucia Sommerova</name>
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<author><name sortKey="Samali, Afshin" sort="Samali, Afshin" uniqKey="Samali A" first="Afshin" last="Samali">Afshin Samali</name>
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<author><name sortKey="Tavernier, Jan" sort="Tavernier, Jan" uniqKey="Tavernier J" first="Jan" last="Tavernier">Jan Tavernier</name>
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<author><name sortKey="Hrstka, Roman" sort="Hrstka, Roman" uniqKey="Hrstka R" first="Roman" last="Hrstka">Roman Hrstka</name>
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<author><name sortKey="Dupont, Aurelien" sort="Dupont, Aurelien" uniqKey="Dupont A" first="Aurélien" last="Dupont">Aurélien Dupont</name>
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<author><name sortKey="Fessart, Delphine" sort="Fessart, Delphine" uniqKey="Fessart D" first="Delphine" last="Fessart">Delphine Fessart</name>
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<author><name sortKey="Delom, Frederic" sort="Delom, Frederic" uniqKey="Delom F" first="Frédéric" last="Delom">Frédéric Delom</name>
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</affiliation>
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<author><name sortKey="Hupp, Ted" sort="Hupp, Ted" uniqKey="Hupp T" first="Ted" last="Hupp">Ted Hupp</name>
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<author><name sortKey="Chatziioannou, Aristotelis" sort="Chatziioannou, Aristotelis" uniqKey="Chatziioannou A" first="Aristotelis" last="Chatziioannou">Aristotelis Chatziioannou</name>
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<author><name sortKey="Chevet, Eric" sort="Chevet, Eric" uniqKey="Chevet E" first="Eric" last="Chevet">Eric Chevet</name>
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<author><name sortKey="Ogier Enis, Eric" sort="Ogier Enis, Eric" uniqKey="Ogier Enis E" first="Eric" last="Ogier-Denis">Eric Ogier-Denis</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">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</title>
<author><name sortKey="Maurel, Marion" sort="Maurel, Marion" uniqKey="Maurel M" first="Marion" last="Maurel">Marion Maurel</name>
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<author><name sortKey="Obacz, Joanna" sort="Obacz, Joanna" uniqKey="Obacz J" first="Joanna" last="Obacz">Joanna Obacz</name>
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<author><name sortKey="Avril, Tony" sort="Avril, Tony" uniqKey="Avril T" first="Tony" last="Avril">Tony Avril</name>
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<author><name sortKey="Ding, Yong Ing" sort="Ding, Yong Ing" uniqKey="Ding Y" first="Yong-Ping" last="Ding">Yong-Ping Ding</name>
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<author><name sortKey="Papadodima, Olga" sort="Papadodima, Olga" uniqKey="Papadodima O" first="Olga" last="Papadodima">Olga Papadodima</name>
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<author><name sortKey="Treton, Xavier" sort="Treton, Xavier" uniqKey="Treton X" first="Xavier" last="Treton">Xavier Treton</name>
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<author><name sortKey="Daniel, Fanny" sort="Daniel, Fanny" uniqKey="Daniel F" first="Fanny" last="Daniel">Fanny Daniel</name>
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<author><name sortKey="Pilalis, Eleftherios" sort="Pilalis, Eleftherios" uniqKey="Pilalis E" first="Eleftherios" last="Pilalis">Eleftherios Pilalis</name>
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</affiliation>
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<author><name sortKey="Horberg, Johanna" sort="Horberg, Johanna" uniqKey="Horberg J" first="Johanna" last="Hörberg">Johanna Hörberg</name>
<affiliation><nlm:aff id="emmm201810120-aff-0010"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hou, Wenyang" sort="Hou, Wenyang" uniqKey="Hou W" first="Wenyang" last="Hou">Wenyang Hou</name>
<affiliation><nlm:aff id="emmm201810120-aff-0011"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Beauchamp, Marie Laude" sort="Beauchamp, Marie Laude" uniqKey="Beauchamp M" first="Marie-Claude" last="Beauchamp">Marie-Claude Beauchamp</name>
<affiliation><nlm:aff id="emmm201810120-aff-0011"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tourneur Arsille, Julien" sort="Tourneur Arsille, Julien" uniqKey="Tourneur Arsille J" first="Julien" last="Tourneur-Marsille">Julien Tourneur-Marsille</name>
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</affiliation>
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<author><name sortKey="Cazals Atem, Dominique" sort="Cazals Atem, Dominique" uniqKey="Cazals Atem D" first="Dominique" last="Cazals-Hatem">Dominique Cazals-Hatem</name>
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</affiliation>
<affiliation><nlm:aff id="emmm201810120-aff-0006"></nlm:aff>
</affiliation>
<affiliation><nlm:aff id="emmm201810120-aff-0007"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sommerova, Lucia" sort="Sommerova, Lucia" uniqKey="Sommerova L" first="Lucia" last="Sommerova">Lucia Sommerova</name>
<affiliation><nlm:aff id="emmm201810120-aff-0012"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Samali, Afshin" sort="Samali, Afshin" uniqKey="Samali A" first="Afshin" last="Samali">Afshin Samali</name>
<affiliation><nlm:aff id="emmm201810120-aff-0004"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Tavernier, Jan" sort="Tavernier, Jan" uniqKey="Tavernier J" first="Jan" last="Tavernier">Jan Tavernier</name>
<affiliation><nlm:aff id="emmm201810120-aff-0003"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hrstka, Roman" sort="Hrstka, Roman" uniqKey="Hrstka R" first="Roman" last="Hrstka">Roman Hrstka</name>
<affiliation><nlm:aff id="emmm201810120-aff-0012"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Dupont, Aurelien" sort="Dupont, Aurelien" uniqKey="Dupont A" first="Aurélien" last="Dupont">Aurélien Dupont</name>
<affiliation><nlm:aff id="emmm201810120-aff-0013"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Fessart, Delphine" sort="Fessart, Delphine" uniqKey="Fessart D" first="Delphine" last="Fessart">Delphine Fessart</name>
<affiliation><nlm:aff id="emmm201810120-aff-0014"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Delom, Frederic" sort="Delom, Frederic" uniqKey="Delom F" first="Frédéric" last="Delom">Frédéric Delom</name>
<affiliation><nlm:aff id="emmm201810120-aff-0014"></nlm:aff>
</affiliation>
</author>
<author><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>
<affiliation><nlm:aff id="emmm201810120-aff-0015"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Jansen, Gregor" sort="Jansen, Gregor" uniqKey="Jansen G" first="Gregor" last="Jansen">Gregor Jansen</name>
<affiliation><nlm:aff id="emmm201810120-aff-0016"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Eriksson, Leif A" sort="Eriksson, Leif A" uniqKey="Eriksson L" first="Leif A" last="Eriksson">Leif A. Eriksson</name>
<affiliation><nlm:aff id="emmm201810120-aff-0010"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Thomas, David Y" sort="Thomas, David Y" uniqKey="Thomas D" first="David Y" last="Thomas">David Y. Thomas</name>
<affiliation><nlm:aff id="emmm201810120-aff-0016"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Jerome Ajewska, Loydie" sort="Jerome Ajewska, Loydie" uniqKey="Jerome Ajewska L" first="Loydie" last="Jerome-Majewska">Loydie Jerome-Majewska</name>
<affiliation><nlm:aff id="emmm201810120-aff-0011"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Hupp, Ted" sort="Hupp, Ted" uniqKey="Hupp T" first="Ted" last="Hupp">Ted Hupp</name>
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</affiliation>
<affiliation><nlm:aff id="emmm201810120-aff-0012"></nlm:aff>
</affiliation>
<affiliation><nlm:aff id="emmm201810120-aff-0017"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Chatziioannou, Aristotelis" sort="Chatziioannou, Aristotelis" uniqKey="Chatziioannou A" first="Aristotelis" last="Chatziioannou">Aristotelis Chatziioannou</name>
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</affiliation>
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</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>
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</affiliation>
</author>
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<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>
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<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>
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<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>
</custom-meta>
</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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