Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 287, Issue 6, Pages 4033-4040Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.280065
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Funding
- National Institutes of Health [A1068685, A1095623, DK35108, DK080506]
- CCFA
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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-1 beta. Deletion of ATG16L1 in mouse embryonic fibroblasts significantly amplifies IL-1 beta 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-1 beta signaling because of the increased p62 level.
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