PXD065587

PXD065587 is an original dataset announced via ProteomeXchange.

Title	Species-specific cleavage of the autophagy adaptor p62 dictates responses to TNF
Description	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.
HostingRepository	PRIDE
AnnounceDate	2026-04-07
AnnouncementXML	Submission_2026-04-07_07:53:55.055.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Sergio Lilla
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2025-06-29 04:07:24	ID requested
⏵ 1	2026-04-07 07:53:55	announced

10.1016/J.MOLCEL.2026.03.013;

submitter keyword: autophagy, TNF, inflammation, caspase, protein cleavge,apoptosis, p62

Kevin Ryan
contact affiliation	CRUK -CRUK Scotland Institute for Cancer Research - Switchback Rd, Bearsden, Glasgow G61 1BD - United Kingdom
contact email	k.ryan@crukscotlandinstitute.ac.uk
lab head
Sergio Lilla
contact affiliation	Proteomics
contact email	s.lilla@beatson.gla.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD065587
     1. Label: PRIDE project
     2. Name: Species-specific cleavage of the autophagy adaptor p62 dictates responses to TNF