IRGM governs the core autophagy machinery to conduct antimicrobial defense

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anti-Infective Agents / metabolism*
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy*
  • Autophagy-Related Protein-1 Homolog
  • Autophagy-Related Proteins
  • Beclin-1
  • Blotting, Western
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Line, Tumor
  • Crohn Disease / genetics
  • Crohn Disease / metabolism*
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / metabolism*
  • Gene Expression
  • HCT116 Cells
  • HEK293 Cells
  • HT29 Cells
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Microscopy, Confocal
  • Nod2 Signaling Adaptor Protein / genetics
  • Nod2 Signaling Adaptor Protein / metabolism
  • Protein Binding
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA Interference
  • Receptors, Pattern Recognition / genetics
  • Receptors, Pattern Recognition / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • U937 Cells
  • Ubiquitination

Substances

  • ATG16L1 protein, human
  • Anti-Infective Agents
  • Apoptosis Regulatory Proteins
  • Autophagy-Related Proteins
  • BECN1 protein, human
  • Beclin-1
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • NOD2 protein, human
  • Nod2 Signaling Adaptor Protein
  • Receptors, Pattern Recognition
  • Autophagy-Related Protein-1 Homolog
  • Protein-Serine-Threonine Kinases
  • ULK1 protein, human
  • GTP-Binding Proteins
  • IRGM protein, human