| Title: |
Species-specific cleavage of the autophagy adaptor p62 dictates responses to TNF |
| Authors: |
Nössing, Christoph; Troitskaya, Olga; Long, Jaclyn S.; Craxton, Andrew; Brucoli, Martina; Anderson, Eve; Lilla, Sergio; McEwan, David G.; Minton, Annabel R.; Barthet, Valentin J.A.; O’Prey, Jim; Thomson, Gemma; Nixon, Colin; Zanivan, Sara; Strathdee, Douglas; MacFarlane, Marion; Ryan, Kevin M. |
| Publisher Information: |
Elsevier (Cell Press) |
| Publication Year: |
2026 |
| Collection: |
University of Glasgow: Enlighten - Publications |
| Description: |
Inflammation can affect many diseases. We report here that inflammatory cytokines invoke caspase-8-mediated cleavage of the autophagy adaptor p62/SQSTM1 at aspartic acid 329 in human cells, producing a previously described truncated form, which we term tr-p62. We show that TNF-driven cell death is tr-p62 dependent and that autophagy inhibition promotes death via tr-p62 accumulation. Mechanistically, p62 cleavage is receptor-interacting serine/threonine-protein kinase 1 (RIPK1) dependent, and tr-p62 stabilizes caspase-8 activating complex-IIb. tr-p62-driven cell death downstream of TNF is also RIPK1 and caspase dependent, promoting feedforward caspase-8 activation. p62 cleavage does not, however, affect necroptosis. Surprisingly, this caspase-8 cleavage site in p62 is absent in mice, and introduction of cleavable forms of p62 into mouse cells causes sensitization to TNF-induced death. Moreover, mice with CRISPR-Cas9-generated cleavable p62 exhibit TNF hypersensitivity and intestinal inflammation in vivo. These findings provide significant insights into TNF-induced cell death and introduce a mouse model that may provide better clarity for human-related studies of inflammatory disease. |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| Relation: |
https://eprints.gla.ac.uk/383318/1/383318.pdf; Nössing, C. et al. (2026) Species-specific cleavage of the autophagy adaptor p62 dictates responses to TNF. Molecular Cell , (doi:10.1016/j.molcel.2026.03.013 ) (In Press) |
| DOI: |
10.1016/j.molcel.2026.03.013 |
| Availability: |
https://eprints.gla.ac.uk/383318/; https://eprints.gla.ac.uk/383318/1/383318.pdf; https://doi.org/10.1016/j.molcel.2026.03.013 |
| Rights: |
cc_by_4 |
| Accession Number: |
edsbas.7EEB0A71 |
| Database: |
BASE |