PXD035392-2

PXD035392 is an original dataset announced via ProteomeXchange.

Title	STUB1 is an intracellular checkpoint for interferon gamma sensing
Description	Immune checkpoint blockade (ICB) leads to durable and complete tumour regression in some patients but in others gives temporary, partial or no response. Accordingly, significant efforts are underway to identify tumour-intrinsic mechanisms underlying ICB resistance. Results from a published CRISPR screen in a mouse model suggested that targeting STUB1, an E3 ligase involved in protein homeostasis, may overcome ICB resistance but the molecular basis of this effect remains unclear. Herein, we report an under-appreciated role of STUB1 to dampen the interferon gamma (IFNg) response. Genetic deletion of STUB1 increased IFNGR1 abundance on the cell surface and thus enhanced the downstream IFNg response as showed by multiple approaches including Western blotting, flow cytometry, qPCR, phospho-STAT1 assay, immunopeptidomics, proteomics, and gene expression profiling. Human prostate and breast cancer cells with STUB1 deletion were also susceptible to cytokine-induced growth inhibition. Furthermore, blockade of STUB1 protein function recapitulated the STUB1-null phenotypes. Despite these encouraging in vitro data and positive implications from clinical datasets, we did not observe in vivo benefits of inactivating Stub1 in mouse syngeneic tumour models - with or without combination with anti-PD-1 therapy. However, our findings elucidate STUB1 as a barrier to IFNg sensing, prompting further investigations to assess if broader inactivation of human STUB1 in both tumors and immune cells could overcome ICB resistance.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:57:07.746.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Simon Ng
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2022-07-20 00:07:20	ID requested
1	2022-08-18 10:53:53	announced
⏵ 2	2023-11-14 08:57:08	announced	2023-11-14: Updated project metadata.

Dataset with its publication pending

submitter keyword: mouse melanoma cell lines

Brian Henry
contact affiliation	MSD Singapore
contact email	brian.henry3@merck.com
lab head
Simon Ng
contact affiliation	MSD Singapore
contact email	sng3@ualberta.ca
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD035392
     1. Label: PRIDE project
     2. Name: STUB1 is an intracellular checkpoint for interferon gamma sensing