PXD057917

PXD057917 is an original dataset announced via ProteomeXchange.

Title	USP5 Stabilizes YTHDF1 to Control Cancer Immune Surveillance through mTORC1-mediated Phosphorylation
Description	The N6-methyladenosine (m6A) binding protein YTHDF1 emerges as a frequently upregulated oncogene across various cancer types. Its depletion significantly improves the efficacy of cancer immune checkpoint blockade (ICB) treatment. A comprehensive understanding of the molecular mechanisms governing YTHDF1 protein stability is pivotal for enhancing clinical response rates and the effectiveness of ICB in cancer patients. Here, we report that USP5 interacts with YTHDF1, removing K11-linked polyubiquitination on multiple lysine residues to stabilize YTHDF1, thereby conferring its oncogenic properties. In response to insulin, mTORC1 phosphorylates USP5 at S149, promoting its dimerization. Dimerized USP5 then binds to YTHDF1, preventing its degradation. Conversely, the CUL7-FBXW8 E3 ubiquitin ligase promotes K11-linked polyubiquitination and degradation of YTHDF1. USP5 and FBXW8 thus regulate YTHDF1 ubiquitylation at defined residues through mutually exclusive interactions and opposing activities. Furthermore, deficiency in YTHDF1 or USP5 enhances PD-L1 expression and compromises the expression of multiple immune response-related genes, fostering cancer immune evasion. Remarkably, combining USP5 inhibitor treatment with anti-PD-L1 immunotherapy reprograms the anti-tumor T-cell immunity environment, leading to enhanced tumor regression and markedly improved overall survival rates in mouse tumor models. Therefore, in hepatocellular carcinoma and lung cancer patients, USP5 may serve as a promising biomarker for stratifying individuals for anti-PD-1 therapy. Our findings reveal a ubiquitination-dependent regulation of YTHDF1 protein stability influencing immune response gene expression, suggesting USP5 inhibition combined with PD-(L)1 blockade as a novel and promising strategy for cancer treatment.
HostingRepository	iProX
AnnounceDate	2024-11-14
AnnouncementXML	Submission_2024-11-14_21:21:16.056.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Lin Zhang
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2024-11-14 21:21:00	ID requested
⏵ 1	2024-11-14 21:21:16	announced

Dataset with its publication pending

submitter keyword: USP5, YTHDF1, cancer immune

Chungang Liu
contact affiliation	Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University
contact email	liuchungang@zju.edu.cn
lab head
Lin Zhang
contact affiliation	Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University
contact email	384336122@qq.com
dataset submitter

iProX dataset URI