Autophagy suppresses interleukin-1β (IL-1β) signaling by activation of p62 degradation via lysosomal and proteasomal pathways.
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.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Autophagy, Carrier Proteins, Cells, Cultured, Cullin Proteins, Embryo, Mammalian, Enzyme Activation, Fibroblasts, Gene Deletion, Heat-Shock Proteins, Interleukin-1beta, Mice, Mice, Knockout, Proteasome Endopeptidase Complex, Signal Transduction
Adaptor Proteins, Signal Transducing, Animals, Autophagy, Carrier Proteins, Cells, Cultured, Cullin Proteins, Embryo, Mammalian, Enzyme Activation, Fibroblasts, Gene Deletion, Heat-Shock Proteins, Interleukin-1beta, Mice, Mice, Knockout, Proteasome Endopeptidase Complex, Signal Transduction
J. Biol. Chem.
Date: Feb. 03, 2012
PubMed ID: 22167182
View in: Pubmed Google Scholar
Download Curated Data For This Publication
134295
Switch View:
- Interactions 3
- PTM Genes 1