Autophagy Suppresses Interleukin-1 beta (IL-1 beta) Signaling by Activation of p62 Degradation via Lysosomal and Proteasomal Pathways

作者：Lee Jongdae^*; Kim Hye Ri; Quinley Christine; Kim Joanna; Gonzalez Navajas Jose; Xavier Ramnik; Raz Eyal

来源：Journal of Biological Chemistry, 2012, 287(6): 4033-4040.

DOI：10.1074/jbc.M111.280065

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.

• 出版日期2012-2-3