IRGM restrains NLRP3 inflammasome activation by mediating its SQSTM1/p62-dependent selective autophagy.
IRGM is an established genetic risk factor for Crohn disease (CD) and several other inflammatory disorders. However, the mechanisms employed by IRGM to restrain the inflammation are not known. In our recent study, we showed that IRGM negatively regulates NLRP3 inflammasome activation. IRGM employs 2 parallel approaches to constrain inflammasome activation. First, IRGM directly interacts with NLRP3 and PYCARD/ASC, and mediates their SQSTM1/p62-dependent macroautophagic/autophagic degradation. Second, IRGM impedes inflammasome assembly by blocking the polymerization of NLRP3 and PYCARD. We also found that IRGM suppresses NLRP3-mediated exacerbated outcomes of dextran sodium sulfate (DSS)-induced colitis in a mouse model. Taken together, this study presents evidence that IRGM can directly regulate inflammation and protect from inflammatory diseases.
['Mehto|Subhash|S|0000-0002-5351-7850', 'Chauhan|Swati|S|0000-0002-0512-653X', 'Jena|Kautilya Kumar|KK|0000-0002-7568-1555', 'Chauhan|Nishant Ranjan|NR|0000-0002-9137-6024', 'Nath|Parej|P|', 'Sahu|Rinku|R|0000-0003-2990-0152', 'Dhar|Kollori|K|0000-0002-0315-7420', 'Das|Saroj Kumar|SK|0000-0002-5717-5333', 'Chauhan|Santosh|S|0000-0001-9167-5107']
D000818:Animals D001343:Autophagy D016264:Dextran Sulfate D058847:Inflammasomes D051379:Mice D000071199:NLR Family, Pyrin Domain-Containing 3 Protein D000071456:Sequestosome-1 Protein
IRGM NLRP3 inflammasome Autophagy Crohn disease IRGM1 inflammatory bowel disease