{"id":77850,"date":"2019-05-23T12:21:52","date_gmt":"2019-05-23T11:21:52","guid":{"rendered":"https:\/\/cri1149.fr\/actualites\/the-pro-inflammatory-role-of-agr2-protein-in-crohns-disease-demonstrated-by-cri\/"},"modified":"2019-05-23T12:21:52","modified_gmt":"2019-05-23T11:21:52","slug":"the-pro-inflammatory-role-of-agr2-protein-in-crohns-disease-demonstrated-by-cri","status":"publish","type":"post","link":"https:\/\/cri1149.fr\/en\/news\/the-pro-inflammatory-role-of-agr2-protein-in-crohns-disease-demonstrated-by-cri\/","title":{"rendered":"The pro-inflammatory role of AGR2 protein in CROHN&#8217;s disease demonstrated by CRI"},"content":{"rendered":"<p style=\"text-align: justify;\"><img loading=\"lazy\" decoding=\"async\" class=\"size-full wp-image-13587 alignleft\" src=\"https:\/\/cri1149.fr\/wp-content\/uploads\/2019\/05\/ogier-1.jpg\" alt=\"\" width=\"268\" height=\"116\" \/><strong>The Ogier-Denis \/ Hugot team working on the intestinal inflammation of CRI has just published an article in EMBO concerning the pro-inflammatory role of AGR2 protein in CRI-demonstrated disease.<\/strong><\/p>\n<p>&nbsp;<\/p>\n<p style=\"text-align: justify;\">Control of anterior GRadient 2 (AGR2) dimerization links endoplasmic reticulum proteostasis to inflammation<\/p>\n<p style=\"text-align: justify;\">Marion Maurel, Joanna Obacz, Tony Avril, Yong\u2010Ping Ding, Olga Papadodima, Xavier Treton, Fanny Daniel, Eleftherios Pilalis, Johanna H\u00f6rberg, Wenyang Hou, Marie\u2010Claude Beauchamp, Julien Tourneur\u2010Marsille, Dominique Cazals\u2010Hatem, Lucia Sommerova, Afshin Samali, Jan Tavernier, Roman Hrstka, Aur\u00e9lien Dupont, Delphine Fessart, Fr\u00e9d\u00e9ric Delom, Martin E Fernandez\u2010Zapico, Gregor Jansen, Leif A Eriksson, David Y Thomas, Loydie Jerome\u2010Majewska, Ted Hupp, Aristotelis Chatziioannou, Eric Chevet, Eric Ogier\u2010Denis<\/p>\n<p style=\"text-align: justify;\">EMBO Molecular Medicine (2019) e10120DOI 10.15252\/emmm.201810120 | Published online 30.04.2019<\/p>\n<h4 style=\"text-align: justify;\">Abstract<\/h4>\n<p style=\"text-align: justify;\">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 spontaneously 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 an original protein\u2013protein interaction screen (ERMIT) 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\u2010inflammatory phenotypes, through either autophagy\u2010dependent processes or secretion of AGR2, respectively. We also demonstrate that in IBD and specifically in patients with Crohn&#8217;s disease, the levels of AGR2 dimerization modulators are selectively deregulated, and this correlates with severity of disease. This study provides molecular insights into the anterior gradient 2 (AGR2) mode of action in the endoplasmic reticulum (ER) with an emphasis on the regulation of AGR2 dimers. Dysregulation of AGR2 dimer formation promotes the secretion of AGR2 monomers and leads to inflammation. The latter will act like a pro-inflammatory chemokine making up a bridge between the intestinal epithelium (source of AGR2) and the underlying immune system. Overall, these data allow to consider AGR2 as a new potential target for Crohn\u2019s disease..<\/p>\n<h4 style=\"text-align: justify;\">R\u00e9sum\u00e9<\/h4>\n<p style=\"text-align: justify;\">Ant\u00e9rior-gradient 2 (AGR2) est une prot\u00e9ine dim\u00e9rique de la famille des prot\u00e9ines disulfides isom\u00e9rases impliqu\u00e9e dans la r\u00e9gulation du contr\u00f4le de qualit\u00e9 des prot\u00e9ines au sein du r\u00e9ticulum endoplasmique (RE). La d\u00e9l\u00e9tion d\u2019AGR2 chez la souris induit une inflammation intestinale spontan\u00e9e et favorise le d\u00e9veloppement des maladies inflammatoires chroniques de l\u2019intestin (MICI). Bien que les effets biologiques soient bien \u00e9tablis, les m\u00e9canismes mol\u00e9culaires de la fonction d\u2019AGR2 vis-\u00e0-vis de l\u2019inflammation restent peu connus. En utilisant une approche originale d\u2019interaction prot\u00e9ine-prot\u00e9ine (ERMIT\u00a0: ER Mammalian protein-protein Interaction Trap) pour identifier des r\u00e9gulateurs cellulaires de la dim\u00e9risation d\u2019AGR2, nous identifions des inducteurs (comme TMED2) et des inhibiteurs de cette dim\u00e9risation. La modulation de la formation du dim\u00e8re d\u2019AGR2 en inhibant ou activant le processus, conduit \u00e0 un ph\u00e9notype pro-inflammatoire par respectivement un processus d\u00e9pendant de l\u2019autophagie et par la s\u00e9cr\u00e9tion pathologique d\u2019AGR2. Nous montrons que les modulateurs de la dim\u00e9risation d\u2019AGR2 sont s\u00e9lectivement d\u00e9r\u00e9gul\u00e9s chez les patients atteints de la maladie de Crohn et corr\u00e8lent avec la s\u00e9v\u00e9rit\u00e9 de la maladie. Cette \u00e9tude d\u00e9voile les m\u00e9canismes d\u2019action d\u2019AGR2 dans le r\u00e9ticulum endoplasmique et sur la r\u00e9gulation de sa dim\u00e9risation. La d\u00e9r\u00e9gulation de la formation du dim\u00e8re provoque la s\u00e9cr\u00e9tion d\u2019AGR2 et conduit \u00e0 l\u2019inflammation. AGR2 se comporterait comme une chemiokine pro-inflammatoire faisant le pont entre l\u2019\u00e9pith\u00e9lium intestinal (source d\u2019AGR2) et le syst\u00e8me immunitaire sous-jacent. Ce travail permet de consid\u00e9rer AGR2 comme une nouvelle cible th\u00e9rapeutique potentielle pour la maladie de Crohn.<\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"size-medium wp-image-13586 aligncenter\" src=\"https:\/\/cri1149.fr\/wp-content\/uploads\/2019\/05\/ogier-300x202.gif\" alt=\"\" width=\"300\" height=\"202\" \/><\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"size-medium wp-image-13586 aligncenter\" src=\"http:\/\/cyber.pixilie.fr\/wp-content\/uploads\/2019\/05\/ogier-300x202.gif\" alt=\"\" width=\"300\" height=\"202\" \/><\/p>\n","protected":false},"excerpt":{"rendered":"<p>The Ogier-Denis \/ Hugot team working on the intestinal inflammation of CRI has just published an article in EMBO concerning the pro-inflammatory role of AGR2 protein in CRI-demonstrated disease. &nbsp; [&hellip;]<\/p>\n","protected":false},"author":9,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"_EventAllDay":false,"_EventTimezone":"","_EventStartDate":"","_EventEndDate":"","_EventStartDateUTC":"","_EventEndDateUTC":"","_EventShowMap":false,"_EventShowMapLink":false,"_EventURL":"","_EventCost":"","_EventCostDescription":"","_EventCurrencySymbol":"","_EventCurrencyCode":"","_EventCurrencyPosition":"","_EventDateTimeSeparator":"","_EventTimeRangeSeparator":"","_EventOrganizerID":[],"_EventVenueID":[],"_OrganizerEmail":"","_OrganizerPhone":"","_OrganizerWebsite":"","_VenueAddress":"","_VenueCity":"","_VenueCountry":"","_VenueProvince":"","_VenueState":"","_VenueZip":"","_VenuePhone":"","_VenueURL":"","_VenueStateProvince":"","_VenueLat":"","_VenueLng":"","_VenueShowMap":false,"_VenueShowMapLink":false,"footnotes":""},"categories":[327,328],"tags":[],"class_list":["post-77850","post","type-post","status-publish","format-standard","hentry","category-news","category-news-of-the-month"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.2 - 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