title: Autophagy suppresses interleukin-1β (IL-1β) signaling by activation of p62 degradation via lysosomal and proteasomal pathways.
abstract: ATG16L1 is an essential component of the autophagasome. The T300A allele of ATG16L1 is associated with the increased susceptibility to Crohn disease. In this study, we identified a novel function of ATG16L1, which suppresses signaling of the pro-inflammatory cytokine IL-1β. Deletion of ATG16L1 in mouse embryonic fibroblasts significantly amplifies IL-1β signal transduction cascades. This amplification is due to elevated p62 levels in ATG16L1-deficient cells. We found that ATG16L1 regulates p62 levels via both autolysosomal and proteasomal pathways. For proteasomal degradation, we found that Cullin-3 (Cul-3) is a E3 ubiquitin ligase of p62 and that ATG16L1 is essential for neddylation of Cul-3, a step required for Cul-3 activation. Taken together our data indicate that loss-of-function of ATG16L1 results in a hyper-responsiveness to the IL-1β signaling because of the increased p62 level.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California 92093-0663, USA. j142lee@ucsd.edu
authors.forename: Jongdae
authors.initials: J
authors.lastname: Lee
authors.forename: Hye Ri
authors.initials: HR
authors.lastname: Kim
authors.forename: Christine
authors.initials: C
authors.lastname: Quinley
authors.forename: Joanna
authors.initials: J
authors.lastname: Kim
authors.forename: Jose
authors.initials: J
authors.lastname: Gonzalez-Navajas
authors.forename: Ramnik
authors.initials: R
authors.lastname: Xavier
authors.forename: Eyal
authors.initials: E
authors.lastname: Raz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D017353:Gene Deletion; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C532820:Atg16l1 protein, mouse; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; C503646:Cul3 protein, mouse; D044842:Cullin Proteins; D006360:Heat-Shock Proteins; D053583:Interleukin-1beta; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D046988:Proteasome Endopeptidase Complex