Cargando…
The Crohn’s Disease Risk Factor IRGM Limits NLRP3 Inflammasome Activation by Impeding Its Assembly and by Mediating Its Selective Autophagy
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...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372082/ https://www.ncbi.nlm.nih.gov/pubmed/30612879 http://dx.doi.org/10.1016/j.molcel.2018.11.018 |
_version_ | 1783394680815222784 |
---|---|
author | Mehto, Subhash Jena, Kautilya Kumar Nath, Parej Chauhan, Swati Kolapalli, Srinivasa Prasad Das, Saroj Kumar Sahoo, Pradyumna Kumar Jain, Ashish Taylor, Gregory A. Chauhan, Santosh |
author_facet | Mehto, Subhash Jena, Kautilya Kumar Nath, Parej Chauhan, Swati Kolapalli, Srinivasa Prasad Das, Saroj Kumar Sahoo, Pradyumna Kumar Jain, Ashish Taylor, Gregory A. Chauhan, Santosh |
author_sort | Mehto, Subhash |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6372082 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-63720822019-02-12 The Crohn’s Disease Risk Factor IRGM Limits NLRP3 Inflammasome Activation by Impeding Its Assembly and by Mediating Its Selective Autophagy Mehto, Subhash Jena, Kautilya Kumar Nath, Parej Chauhan, Swati Kolapalli, Srinivasa Prasad Das, Saroj Kumar Sahoo, Pradyumna Kumar Jain, Ashish Taylor, Gregory A. Chauhan, Santosh Mol Cell Article 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. Cell Press 2019-02-07 /pmc/articles/PMC6372082/ /pubmed/30612879 http://dx.doi.org/10.1016/j.molcel.2018.11.018 Text en © 2018 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Mehto, Subhash Jena, Kautilya Kumar Nath, Parej Chauhan, Swati Kolapalli, Srinivasa Prasad Das, Saroj Kumar Sahoo, Pradyumna Kumar Jain, Ashish Taylor, Gregory A. Chauhan, Santosh The Crohn’s Disease Risk Factor IRGM Limits NLRP3 Inflammasome Activation by Impeding Its Assembly and by Mediating Its Selective Autophagy |
title | The Crohn’s Disease Risk Factor IRGM Limits NLRP3 Inflammasome Activation by Impeding Its Assembly and by Mediating Its Selective Autophagy |
title_full | The Crohn’s Disease Risk Factor IRGM Limits NLRP3 Inflammasome Activation by Impeding Its Assembly and by Mediating Its Selective Autophagy |
title_fullStr | The Crohn’s Disease Risk Factor IRGM Limits NLRP3 Inflammasome Activation by Impeding Its Assembly and by Mediating Its Selective Autophagy |
title_full_unstemmed | The Crohn’s Disease Risk Factor IRGM Limits NLRP3 Inflammasome Activation by Impeding Its Assembly and by Mediating Its Selective Autophagy |
title_short | The Crohn’s Disease Risk Factor IRGM Limits NLRP3 Inflammasome Activation by Impeding Its Assembly and by Mediating Its Selective Autophagy |
title_sort | crohn’s disease risk factor irgm limits nlrp3 inflammasome activation by impeding its assembly and by mediating its selective autophagy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372082/ https://www.ncbi.nlm.nih.gov/pubmed/30612879 http://dx.doi.org/10.1016/j.molcel.2018.11.018 |
work_keys_str_mv | AT mehtosubhash thecrohnsdiseaseriskfactorirgmlimitsnlrp3inflammasomeactivationbyimpedingitsassemblyandbymediatingitsselectiveautophagy AT jenakautilyakumar thecrohnsdiseaseriskfactorirgmlimitsnlrp3inflammasomeactivationbyimpedingitsassemblyandbymediatingitsselectiveautophagy AT nathparej thecrohnsdiseaseriskfactorirgmlimitsnlrp3inflammasomeactivationbyimpedingitsassemblyandbymediatingitsselectiveautophagy AT chauhanswati thecrohnsdiseaseriskfactorirgmlimitsnlrp3inflammasomeactivationbyimpedingitsassemblyandbymediatingitsselectiveautophagy AT kolapallisrinivasaprasad thecrohnsdiseaseriskfactorirgmlimitsnlrp3inflammasomeactivationbyimpedingitsassemblyandbymediatingitsselectiveautophagy AT dassarojkumar thecrohnsdiseaseriskfactorirgmlimitsnlrp3inflammasomeactivationbyimpedingitsassemblyandbymediatingitsselectiveautophagy AT sahoopradyumnakumar thecrohnsdiseaseriskfactorirgmlimitsnlrp3inflammasomeactivationbyimpedingitsassemblyandbymediatingitsselectiveautophagy AT jainashish thecrohnsdiseaseriskfactorirgmlimitsnlrp3inflammasomeactivationbyimpedingitsassemblyandbymediatingitsselectiveautophagy AT taylorgregorya thecrohnsdiseaseriskfactorirgmlimitsnlrp3inflammasomeactivationbyimpedingitsassemblyandbymediatingitsselectiveautophagy AT chauhansantosh thecrohnsdiseaseriskfactorirgmlimitsnlrp3inflammasomeactivationbyimpedingitsassemblyandbymediatingitsselectiveautophagy AT mehtosubhash crohnsdiseaseriskfactorirgmlimitsnlrp3inflammasomeactivationbyimpedingitsassemblyandbymediatingitsselectiveautophagy AT jenakautilyakumar crohnsdiseaseriskfactorirgmlimitsnlrp3inflammasomeactivationbyimpedingitsassemblyandbymediatingitsselectiveautophagy AT nathparej crohnsdiseaseriskfactorirgmlimitsnlrp3inflammasomeactivationbyimpedingitsassemblyandbymediatingitsselectiveautophagy AT chauhanswati crohnsdiseaseriskfactorirgmlimitsnlrp3inflammasomeactivationbyimpedingitsassemblyandbymediatingitsselectiveautophagy AT kolapallisrinivasaprasad crohnsdiseaseriskfactorirgmlimitsnlrp3inflammasomeactivationbyimpedingitsassemblyandbymediatingitsselectiveautophagy AT dassarojkumar crohnsdiseaseriskfactorirgmlimitsnlrp3inflammasomeactivationbyimpedingitsassemblyandbymediatingitsselectiveautophagy AT sahoopradyumnakumar crohnsdiseaseriskfactorirgmlimitsnlrp3inflammasomeactivationbyimpedingitsassemblyandbymediatingitsselectiveautophagy AT jainashish crohnsdiseaseriskfactorirgmlimitsnlrp3inflammasomeactivationbyimpedingitsassemblyandbymediatingitsselectiveautophagy AT taylorgregorya crohnsdiseaseriskfactorirgmlimitsnlrp3inflammasomeactivationbyimpedingitsassemblyandbymediatingitsselectiveautophagy AT chauhansantosh crohnsdiseaseriskfactorirgmlimitsnlrp3inflammasomeactivationbyimpedingitsassemblyandbymediatingitsselectiveautophagy |