The protein ATG16L1 suppresses inflammatory cytokines induced by the intracellular sensors Nod1 and Nod2 in an autophagy-independent manner.
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.
Department of Immunology, University of Toronto, Toronto M5S1A8, Canada.
Matthew T
MT
Sorbara
Lisa K
LK
Ellison
Mahendrasingh
M
Ramjeet
Leonardo H
LH
Travassos
Nicola L
NL
Jones
Stephen E
SE
Girardin
Dana J
DJ
Philpott
D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071187:Autophagy-Related Protein 5; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D020022:Genetic Predisposition to Disease; D006801:Humans; D007249:Inflammation; D007413:Intestinal Mucosa / Q000166:cytology; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000502:physiology; D053474:Nod1 Signaling Adaptor Protein / Q000502:physiology*; D053473:Nod2 Signaling Adaptor Protein / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D054875:Ubiquitination
C518959:ATG16L1 protein, human; C532820:Atg16l1 protein, mouse; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D016207:Cytokines; D008869:Microtubule-Associated Proteins; C119067:NOD1 protein, human; C429018:NOD2 protein, human; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D034741:RNA, Small Interfering; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506255:Ripk2 protein, mouse