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Mol Cell. 2019 Feb 7;73(3):429-445.e7. doi: 10.1016/j.molcel.2018.11.018. Epub 2019 Jan 3.

The Crohn's Disease Risk Factor IRGM Limits NLRP3 Inflammasome Activation by Impeding Its Assembly and by Mediating Its Selective Autophagy.

Author information

1
Cell Biology and Infectious Diseases Unit, Institute of Life Sciences, Bhubaneswar 751023, India.
2
Cell Biology and Infectious Diseases Unit, Institute of Life Sciences, Bhubaneswar 751023, India; School of Biotechnology, KIIT University, Bhubaneswar 751024, India.
3
Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
4
Geriatric Research, Education, and Clinical Center, VA Medical Center, Durham, NC 27705, USA.
5
Cell Biology and Infectious Diseases Unit, Institute of Life Sciences, Bhubaneswar 751023, India. Electronic address: schauhan@ils.res.in.

Abstract

Several large-scale genome-wide association studies genetically linked IRGM to Crohn's disease and other inflammatory disorders in which the IRGM appears to have a protective function. However, the mechanism by which IRGM accomplishes this anti-inflammatory role remains unclear. Here, we reveal that IRGM/Irgm1 is a negative regulator of the NLRP3 inflammasome activation. We show that IRGM expression, which is increased by PAMPs, DAMPs, and microbes, can suppress the pro-inflammatory responses provoked by the same stimuli. IRGM/Irgm1 negatively regulates IL-1β maturation by suppressing the activation of the NLRP3 inflammasome. Mechanistically, we show that IRGM interacts with NLRP3 and ASC and hinders inflammasome assembly by blocking their oligomerization. Further, IRGM mediates selective autophagic degradation of NLRP3 and ASC. By suppressing inflammasome activation, IRGM/Irgm1 protects from pyroptosis and gut inflammation in a Crohn's disease experimental mouse model. This study for the first time identifies the mechanism by which IRGM is protective against inflammatory disorders.

KEYWORDS:

ASC; Crohn’s disease; IRGM; Irgm1; NLRP3; autoimmunity; autophagy; inflammasome; inflammatory bowel diseases; inflammatory disorders; p62

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