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Ubiquitin ligase STUB1 destabilizes IFNγ-receptor complex to suppress tumor IFNγ signaling
- Source :
- Nature Communications, 13(1), 1. Nature Publishing Group
- Publication Year :
- 2022
-
Abstract
- The cytokine IFNγ differentially impacts on tumors upon immune checkpoint blockade (ICB). Despite our understanding of downstream signaling events, less is known about regulation of its receptor (IFNγ-R1). With an unbiased genome-wide CRISPR/Cas9 screen for critical regulators of IFNγ-R1 cell surface abundance, we identify STUB1 as an E3 ubiquitin ligase for IFNγ-R1 in complex with its signal-relaying kinase JAK1. STUB1 mediates ubiquitination-dependent proteasomal degradation of IFNγ-R1/JAK1 complex through IFNγ-R1K285 and JAK1K249. Conversely, STUB1 inactivation amplifies IFNγ signaling, sensitizing tumor cells to cytotoxic T cells in vitro. This is corroborated by an anticorrelation between STUB1 expression and IFNγ response in ICB-treated patients. Consistent with the context-dependent effects of IFNγ in vivo, anti-PD-1 response is increased in heterogenous tumors comprising both wildtype and STUB1-deficient cells, but not full STUB1 knockout tumors. These results uncover STUB1 as a critical regulator of IFNγ-R1, and highlight the context-dependency of STUB1-regulated IFNγ signaling for ICB outcome.
- Subjects :
- Multidisciplinary
Science & Technology
INTERFERON-GAMMA
IDENTIFICATION
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
CHIP
CTLA-4 BLOCKADE
CLINICAL-RESPONSE
General Physics and Astronomy
PROTEIN
General Chemistry
Physics and Astronomy(all)
PD-1 BLOCKADE
Biochemistry
General Biochemistry, Genetics and Molecular Biology
Multidisciplinary Sciences
COMBINED NIVOLUMAB
T-CELLS
Science & Technology - Other Topics
ACQUIRED-RESISTANCE
Genetics and Molecular Biology(all)
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 13
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....3a004bb05a09310ed78358eb9c3637ce