PXD073919

PXD073919 is an original dataset announced via ProteomeXchange.

Title	HERC4-mediated ubiquitination licenses RIPK1 to initiate TNF-induced cell death
Description	TNF can activate both pro-survival and pro-death signaling downstream of TNFR1. Survival signaling originates from TNFR1-containing membrane-bound Complex I, while death signaling is driven by cytosolic Complex II. RIPK1 is a central component of both complexes, but the molecular switch converting RIPK1 from a pro-survival scaffold in Complex I to a pro-death kinase in Complex II has remained elusive. Here, we identify the E3 ligase HERC4 as this crucial switch. HERC4 binds Complex-I-derived S166-phosphorylated, kinase-active RIPK1 and ubiquitinates it within its death domain. This enables RIPK1 oligomerization and assembly of the apoptosis-inducing RIPK1–FADD–caspase-8-containing Complex IIa and, upon caspase inhibition, formation of the necroptosis-initiating RIPK1–RIPK3-containing necrosome. HERC4 deficiency protects mice from TNF-induced systemic inflammatory response syndrome and acute liver injury. HERC4 is thus the missing link enabling Complex I-derived kinase-active RIPK1 to initiate death signaling and represents a previously unrecognized therapeutic entry point for cell-death-dependent TNF-induced inflammatory diseases.
HostingRepository	iProX
AnnounceDate	2026-02-02
AnnouncementXML	Submission_2026-07-20_00:58:40.392.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Tongde Du
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2026-02-02 01:20:00	ID requested
⏵ 1	2026-07-20 00:58:41	announced

Dataset with its publication pending

submitter keyword: HERC4, RIPK1, RIPK1 S166, TNF, apoptosis, necroptosis

Sudan He
contact affiliation	Suzhou Institute of Systems Medicine
contact email	hesudan2018@163.com
lab head
Tongde Du
contact affiliation	Suzhou Institute of Systems Medicine
contact email	dutongde123@163.com
dataset submitter

iProX dataset URI