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

ABSTRACT: Inflammation is a driver of many diseases including cancer. Several studies have also shown that changes to macroautophagy can affect inflammation. We were interested in these connections and we report here that the autophagy adaptor proteins p62/SQSTM1 is cleaved upon treatment with the inflammatory cytokine TNF. Mass spectrometry and CRISPR analysis revealed this cleavage occurs at D329 and is mediated by caspase-8, to produce a short form of p63, which we term tr-p62. Our further analysis showed that cell death induced by TNF in the presence of Smac mimetics is not only dependent on p62, but intrinsically on its cleavage by caspase-8. Moreover, as inhibition of autophagy causes p62 accumulation and sensitizes cell to death, we show that this effect is also dependent on the production of tr-p62. Mechanistically, we show that tr-p62 is cleaved within and mediates a more stable caspase-8 activating complex, leading to a feed-forward loop of caspase-8 activation. Surprisingly, however, we found that mice belong to a very small group of mammals in which this caspase-8 cleavage site in p62 is absent. Introduction of either human p62 or a mutated cleavable version of mouse p62 into mouse cells renders them significantly more sensitive to cell death induced by TNF. Furthermore, we used CRISPR/Cas9 technology to make p62 cleavable on mice and we show that these mice are intrinsically sensitive to treatment with TNF. These findings therefore not only highlight a significant new step in the activation of cell death by TNF, but also provide a new mouse model that may provide better clarity for studies of mouse models of inflammatory disease.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Prostate Gland

DISEASE(S): Inflammation,Cancer

SUBMITTER: Sergio Lilla  

LAB HEAD: Kevin Ryan

PROVIDER: PXD065587 | Pride | 2026-04-07

REPOSITORIES: Pride