The protein ATG16L1 suppresses inflammatory cytokines induced by the intracellular sensors Nod1 and Nod2 in an autophagy-independent manner

Immunity. 2013 Nov 14;39(5):858-73. doi: 10.1016/j.immuni.2013.10.013.

Abstract

The peptidoglycan sensor Nod2 and the autophagy protein ATG16L1 have been linked to Crohn's disease (CD). Although Nod2 and the related sensor, Nod1, direct ATG16L1 to initiate anti-bacterial autophagy, whether ATG16L1 affects Nod-driven inflammation has not been examined. Here, we uncover an unanticipated autophagy-independent role for ATG16L1 in negatively regulating Nod-driven inflammatory responses. Knockdown of ATG16L1 expression, but not that of ATG5 or ATG9a, specifically enhanced Nod-driven cytokine production. In addition, autophagy-incompetent truncated forms of ATG16L1 regulated Nod-driven cytokine responses. Mechanistically, we demonstrated that ATG16L1 interfered with poly-ubiquitination of the Rip2 adaptor and recruitment of Rip2 into large signaling complexes. The CD-associated allele of ATG16L1 was impaired in its ability to regulate Nod-driven inflammatory responses. Overall, these results suggest that ATG16L1 is critical for Nod-dependent regulation of cytokine responses and that disruption of this Nod1- or Nod2-ATG16L1 signaling axis could contribute to the chronic inflammation associated with CD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / physiology*
  • Autophagy-Related Protein 5
  • Autophagy-Related Proteins
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology*
  • Cell Line
  • Crohn Disease / genetics
  • Crohn Disease / immunology
  • Crohn Disease / pathology
  • Cytokines / biosynthesis*
  • Cytokines / genetics
  • Epithelial Cells / immunology
  • Epithelial Cells / metabolism
  • Epithelial Cells / microbiology
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • Genetic Predisposition to Disease
  • Humans
  • Inflammation
  • Intestinal Mucosa / cytology
  • Mice
  • Microtubule-Associated Proteins / deficiency
  • Microtubule-Associated Proteins / physiology
  • Nod1 Signaling Adaptor Protein / physiology*
  • Nod2 Signaling Adaptor Protein / physiology*
  • Protein Processing, Post-Translational
  • RNA Interference
  • RNA, Small Interfering / pharmacology
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Signal Transduction
  • Ubiquitination

Substances

  • ATG16L1 protein, human
  • Atg16l1 protein, mouse
  • Atg5 protein, mouse
  • Autophagy-Related Protein 5
  • Autophagy-Related Proteins
  • Carrier Proteins
  • Cytokines
  • Microtubule-Associated Proteins
  • NOD1 protein, human
  • NOD2 protein, human
  • Nod1 Signaling Adaptor Protein
  • Nod1 protein, mouse
  • Nod2 Signaling Adaptor Protein
  • Nod2 protein, mouse
  • RNA, Small Interfering
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk2 protein, mouse