Species-specific cleavage of the autophagy adaptor p62 dictates responses to TNF

Inflammatory cytokines can induce the cleavage of p62/SQSTM1, resulting in a truncated form termed tr-p62.

• Caspase-8-mediated cleavage of p62 occurs at aspartic acid 329 in human cells, producing tr-p62.
• Cell death driven by TNF is dependent on the presence of tr-p62, with autophagy inhibition leading to increased levels of tr-p62 and enhanced cell death.
• The cleavage of p62 is dependent on receptor-interacting serine/threonine-protein kinase 1 (RIPK1), which also stabilizes a complex that activates caspase-8.
• Caspase-8 activation through tr-p62 contributes to a feedforward mechanism of cell death downstream of TNF, while p62 cleavage does not influence necroptosis.
• Mice lacking the cleavable form of p62 show increased sensitivity to TNF-induced cell death and exhibit intestinal inflammation when cleavable forms are introduced.

AI simplified