IRGM restrains NLRP3 inflammasome activation by mediating its SQSTM1/p62-dependent selective autophagy

ABSTRACT

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.

KEYWORDS:

• Autophagy
• Crohn disease
• inflammatory bowel disease
• IRGM
• IRGM1
• NLRP3 inflammasome

Acknowledgments

This work is supported by the Wellcome Trust/Department of Biotechnology (DBT) India Alliance (IA/I/15/2/502071) fellowship, ILS core funding (Department of Biotechnology, India), and Early Career Reward (SERB, ECR/2016/000478) to Santosh Chauhan. Subhash Mehto is supported by a fellowship from SERB (NPDF, PDF/2016/001697). Swati Chauhan is supported by a fellowship from DST (SR/WOS-A/LS-9/2016).

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the Wellcome Trust/Department of Biotechnology (DBT) India Alliance [IA/I/15/2/502071].