Ubiquitin ligase STUB1 destabilizes IFNγ-receptor complex to suppress tumor IFNγ signaling.
Ubiquitin ligase STUB1 destabilizes IFNγ-receptor complex to suppress tumor IFNγ signaling.
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DOI：
10.1038/s41467-022-29442-x
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发表时间：
2022-04-08
影响因子：
16.6
通讯作者：
Peeper DS
中科院分区：
文献类型：
--
作者：
Apriamashvili G;Vredevoogd DW;Krijgsman O;Bleijerveld OB;Ligtenberg MA;de Bruijn B;Boshuizen J;Traets JJH;D'Empaire Altimari D;van Vliet A;Lin CP;Visser NL;Londino JD;Sanchez-Hodge R;Oswalt LE;Altinok S;Schisler JC;Altelaar M;Peeper DS
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. The IFNγ response pathway is associated with response to immunotherapy in cancer. Here the authors show that high levels of the IFNγ-receptor (IFNγ-R1) affect the outcome of immunotherapy in a context-dependent fashion and identify the E3 ubiquitin ligase STUB1 as a negative regulator of IFNγ-R1/JAK1 expression in cancer cells.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
DOI：
10.1016/j.str.2016.03.023
发表时间：
2016-06-07
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
Ferrao R;Wallweber HJ;Ho H;Tam C;Franke Y;Quinn J;Lupardus PJ
通讯作者：
Lupardus PJ
影响因子：
64.5
作者：
Benci JL;Xu B;Qiu Y;Wu TJ;Dada H;Twyman-Saint Victor C;Cucolo L;Lee DSM;Pauken KE;Huang AC;Gangadhar TC;Amaravadi RK;Schuchter LM;Feldman MD;Ishwaran H;Vonderheide RH;Maity A;Wherry EJ;Minn AJ
通讯作者：
Minn AJ
影响因子：
32.4
作者：
DIGHE, AS;RICHARDS, E;SCHREIBER, RD
通讯作者：
SCHREIBER, RD
影响因子：
21.3
作者：
Connell, P;Ballinger, CA;Patterson, C
通讯作者：
Patterson, C