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Mol Cell. 2015 May 7;58(3):507-21. doi: 10.1016/j.molcel.2015.03.020. Epub 2015 Apr 16.

IRGM governs the core autophagy machinery to conduct antimicrobial defense.

Author information

1
Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA. Electronic address: schauhan1@salud.unm.edu.
2
Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA.
3
Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, NM 87131, USA. Electronic address: vderetic@salud.unm.edu.

Abstract

IRGM, encoded by a uniquely human gene conferring risk for inflammatory diseases, affects autophagy through an unknown mechanism. Here, we show how IRGM controls autophagy. IRGM interacts with ULK1 and Beclin 1 and promotes their co-assembly thus governing the formation of autophagy initiation complexes. We further show that IRGM interacts with pattern recognition receptors including NOD2. IRGM, NOD2, and ATG16L1, all of which are Crohn's disease risk factors, form a molecular complex to modulate autophagic responses to microbial products. NOD2 enhances K63-linked polyubiquitination of IRGM, which is required for interactions of IRGM with the core autophagy factors and for microbial clearance. Thus, IRGM plays a direct role in organizing the core autophagy machinery to endow it with antimicrobial and anti-inflammatory functions.

PMID:
25891078
PMCID:
PMC4427528
DOI:
10.1016/j.molcel.2015.03.020
[Indexed for MEDLINE]
Free PMC Article

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