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

Publication ,  Journal Article
Mehto, S; Jena, KK; Nath, P; Chauhan, S; Kolapalli, SP; Das, SK; Sahoo, PK; Jain, A; Taylor, GA; Chauhan, S
Published in: Mol Cell
February 7, 2019

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.

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Published In

Mol Cell

DOI

EISSN

1097-4164

Publication Date

February 7, 2019

Volume

73

Issue

3

Start / End Page

429 / 445.e7

Location

United States

Related Subject Headings

  • THP-1 Cells
  • Signal Transduction
  • Pyroptosis
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Inflammation Mediators
  • Inflammasomes
  • Humans
  • HT29 Cells
 

Citation

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MLA
NLM
Mehto, S., Jena, K. K., Nath, P., Chauhan, S., Kolapalli, S. P., Das, S. K., … Taylor, G. A. (2019). The Crohn's Disease Risk Factor IRGM Limits NLRP3 Inflammasome Activation by Impeding Its Assembly and by Mediating Its Selective Autophagy. Mol Cell, 73(3), 429-445.e7. https://doi.org/10.1016/j.molcel.2018.11.018
Mehto, Subhash, Kautilya Kumar Jena, Parej Nath, Swati Chauhan, Srinivasa Prasad Kolapalli, Saroj Kumar Das, Pradyumna Kumar Sahoo, Ashish Jain, Gregory A. Taylor, and Santosh Chauhan. “The Crohn's Disease Risk Factor IRGM Limits NLRP3 Inflammasome Activation by Impeding Its Assembly and by Mediating Its Selective Autophagy.Mol Cell 73, no. 3 (February 7, 2019): 429-445.e7. https://doi.org/10.1016/j.molcel.2018.11.018.
Mehto S, Jena KK, Nath P, Chauhan S, Kolapalli SP, Das SK, et al. The Crohn's Disease Risk Factor IRGM Limits NLRP3 Inflammasome Activation by Impeding Its Assembly and by Mediating Its Selective Autophagy. Mol Cell. 2019 Feb 7;73(3):429-445.e7.
Mehto, Subhash, et al. “The Crohn's Disease Risk Factor IRGM Limits NLRP3 Inflammasome Activation by Impeding Its Assembly and by Mediating Its Selective Autophagy.Mol Cell, vol. 73, no. 3, Feb. 2019, pp. 429-445.e7. Pubmed, doi:10.1016/j.molcel.2018.11.018.
Mehto S, Jena KK, Nath P, Chauhan S, Kolapalli SP, Das SK, Sahoo PK, Jain A, Taylor GA. The Crohn's Disease Risk Factor IRGM Limits NLRP3 Inflammasome Activation by Impeding Its Assembly and by Mediating Its Selective Autophagy. Mol Cell. 2019 Feb 7;73(3):429-445.e7.
Journal cover image

Published In

Mol Cell

DOI

EISSN

1097-4164

Publication Date

February 7, 2019

Volume

73

Issue

3

Start / End Page

429 / 445.e7

Location

United States

Related Subject Headings

  • THP-1 Cells
  • Signal Transduction
  • Pyroptosis
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Inflammation Mediators
  • Inflammasomes
  • Humans
  • HT29 Cells