Autophagy suppresses interleukin-1? (IL-1?) 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-1?. Deletion of ATG16L1 in mouse embryonic fibroblasts significantly amplifies IL-1? 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? signaling because of the increased p62 level.

SUBMITTER: Lee J 

PROVIDER: S-EPMC3281713 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature