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...

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Bibliographic Details
Published in:Autophagy 2019-09, Vol.15 (9), p.1645-1647
Main Authors: Mehto, Subhash, Chauhan, Swati, Jena, Kautilya Kumar, Chauhan, Nishant Ranjan, Nath, Parej, Sahu, Rinku, Dhar, Kollori, Das, Saroj Kumar, Chauhan, Santosh
Format: Article
Language:English
Subjects:
Animals
Autophagy
Crohn disease
Dextran Sulfate
Inflammasomes
inflammatory bowel disease
IRGM
IRGM1
Mice
NLR Family, Pyrin Domain-Containing 3 Protein
NLRP3 inflammasome
Sequestosome-1 Protein
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Summary: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.
ISSN:1554-8627
1554-8635
DOI:10.1080/15548627.2019.1628544