Ubiquitin ligase STUB1 destabilizes IFNγ-receptor complex to suppress tumor IFNγ signaling

Georgi Apriamashvili, David W. Vredevoogd, Oscar Krijgsman, Onno B. Bleijerveld, Maarten A. Ligtenberg, Beaunelle Bruijn, Julia Boshuizen, Joleen J. H. Traets, Daniela D’Empaire Altimari, Alex Vliet, Chun-Pu Lin, Nils L. Visser, James D. Londino, Rebekah Sanchez-Hodge, Leah E. Oswalt, Selin Altinok, Jonathan C. Schisler, Maarten Altelaar and Daniel S. Peeper ()
Additional contact information
Georgi Apriamashvili: The Netherlands Cancer Institute
David W. Vredevoogd: The Netherlands Cancer Institute
Oscar Krijgsman: The Netherlands Cancer Institute
Onno B. Bleijerveld: The Netherlands Cancer Institute
Maarten A. Ligtenberg: The Netherlands Cancer Institute
Beaunelle Bruijn: The Netherlands Cancer Institute
Julia Boshuizen: The Netherlands Cancer Institute
Joleen J. H. Traets: The Netherlands Cancer Institute
Daniela D’Empaire Altimari: The Netherlands Cancer Institute
Alex Vliet: The Netherlands Cancer Institute
Chun-Pu Lin: The Netherlands Cancer Institute
Nils L. Visser: The Netherlands Cancer Institute
James D. Londino: The Ohio State University Wexner Medical Center
Rebekah Sanchez-Hodge: The University of North Carolina at Chapel Hill
Leah E. Oswalt: The University of North Carolina at Chapel Hill
Selin Altinok: The University of North Carolina at Chapel Hill
Jonathan C. Schisler: The University of North Carolina at Chapel Hill
Maarten Altelaar: The Netherlands Cancer Institute
Daniel S. Peeper: The Netherlands Cancer Institute

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29442-x

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