p62 cleavage: a species-specific twist in TNF signalling

Macroautophagy (hereafter referred to as autophagy) plays a key role in maintaining cellular homeostasis and shaping response to stress and inflammation. We outline here that inflammatory cytokines trigger caspase-8-dependent cleavage of the autophagy adaptor protein p62/SQSTM1 at aspartic acid 329 generating a truncated form (tr-p62). Tr-p62 enhanced TNF-induced cell death by stabilizing the RIPK1-dependent complex-IIb and amplifying caspase-8 activation, while having no detectable effect on necroptosis. Blocking autophagy leads to tr-p62 accumulation and increased TNF-induced cell death, while non-cleavable p62 reduced autophagic responses and TNF sensitivity. Interestingly, mice naturally lack the caspase-8 cleavage site in p62 and restoring a cleavable version of p62 sensitized mouse cells to TNF-induced cell death. In addition, mice with cleavable p62 showed heightened sensitivity to TNF-induced toxic shock and chemical colitis in vivo. These findings identify p62 cleavage as a key regulator linking autophagy to TNF-driven inflammatory cell death and highlight an important species-specific difference that may influence the interpretation of inflammatory disease models.Abbreviation: DSS: dextran sulfate sodium; FADD: Fas-associated death domain protein; LC3: microtubule-associated protein 1A/1B-light chain 3; PROTAC: proteolysis-targeting chimera; RIPK1: receptor-interacting serine/threonine-protein kinase 1; SMAC: second mitochondria-derived activator of caspases; TNF: tumour necrosis factor; TRAIL: TNF-related apoptosis-inducing ligand.