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02741nam a2200505Ia 4500 |
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10-1038-s41467-022-29442-x |
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220425s2022 CNT 000 0 und d |
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|a 20411723 (ISSN)
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| 245 |
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|a Ubiquitin ligase STUB1 destabilizes IFNγ-receptor complex to suppress tumor IFNγ signaling
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| 260 |
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|b Nature Research
|c 2022
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| 856 |
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|z View Fulltext in Publisher
|u https://doi.org/10.1038/s41467-022-29442-x
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|a 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. © 2022, The Author(s).
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|a genetics
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|a human
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|a Humans
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|a metabolism
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|a signal transduction
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|a Signal Transduction
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|a STUB1 protein, human
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|a ubiquitin
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|a Ubiquitin
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|a ubiquitin protein ligase
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| 650 |
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|a ubiquitination
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| 650 |
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|a Ubiquitination
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| 650 |
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|a Ubiquitin-Protein Ligases
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| 700 |
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|a Altelaar, M.
|e author
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|a Altinok, S.
|e author
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|a Apriamashvili, G.
|e author
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|a Bleijerveld, O.B.
|e author
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|a Boshuizen, J.
|e author
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|a D’Empaire Altimari, D.
|e author
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| 700 |
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|a de Bruijn, B.
|e author
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| 700 |
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|a Krijgsman, O.
|e author
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| 700 |
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|a Ligtenberg, M.A.
|e author
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| 700 |
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|a Lin, C.-P.
|e author
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| 700 |
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|a Londino, J.D.
|e author
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|a Oswalt, L.E.
|e author
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| 700 |
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|a Peeper, D.S.
|e author
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| 700 |
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|a Sanchez-Hodge, R.
|e author
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| 700 |
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|a Schisler, J.C.
|e author
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| 700 |
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|a Traets, J.J.H.
|e author
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| 700 |
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|a van Vliet, A.
|e author
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|a Visser, N.L.
|e author
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|a Vredevoogd, D.W.
|e author
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| 773 |
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|t Nature Communications
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