TY - JOUR
T1 - Ubiquitin ligase STUB1 destabilizes IFNγ-receptor complex to suppress tumor IFNγ signaling
AU - Apriamashvili, Georgi
AU - Vredevoogd, David W.
AU - Krijgsman, Oscar
AU - Bleijerveld, Onno B.
AU - Ligtenberg, Maarten A.
AU - de Bruijn, Beaunelle
AU - Boshuizen, Julia
AU - Traets, Joleen J.H.
AU - D’Empaire Altimari, Daniela
AU - van Vliet, Alex
AU - Lin, Chun Pu
AU - Visser, Nils L.
AU - Londino, James D.
AU - Sanchez-Hodge, Rebekah
AU - Oswalt, Leah E.
AU - Altinok, Selin
AU - Schisler, Jonathan C.
AU - Altelaar, Maarten
AU - Peeper, Daniel S.
N1 - Funding Information:
We thank all members of the Peeper lab as well as of the Division of Molecular Oncology and Immunology for constructive feedback and valuable input. We thank R. Mezzadra, C. Sun, M. Toebes, T. Schumacher, J. Staring, T. Brummelkamp, A. Thouin and J. Jacobs for sharing reagents and cell lines. Furthermore, we thank the flow cytometry, proteomics and sequencing core facilities as well as the animal housing facility and the animal pathology department of The Netherlands Cancer Institute for their support. O.B.B and M.A. acknowledge support of the X-omics Initiative, part of the NWO National Roadmap for Large-Scale Research Infrastructures. J.D.L. was recipient of American Heart Grant 17POST33410945. J.C.S was recipient of National Institute on Aging Grant R01AG066710 and R01AG061188. D.S.P. is funded by the Oncode Institute, which is partly financed by the Dutch Cancer Society.
Funding Information:
We thank all members of the Peeper lab as well as of the Division of Molecular Oncology and Immunology for constructive feedback and valuable input. We thank R. Mezzadra, C. Sun, M. Toebes, T. Schumacher, J. Staring, T. Brummelkamp, A. Thouin and J. Jacobs for sharing reagents and cell lines. Furthermore, we thank the flow cytometry, proteomics and sequencing core facilities as well as the animal housing facility and the animal pathology department of The Netherlands Cancer Institute for their support. O.B.B and M.A. acknowledge support of the X-omics Initiative, part of the NWO National Roadmap for Large-Scale Research Infrastructures. J.D.L. was recipient of American Heart Grant 17POST33410945. J.C.S was recipient of National Institute on Aging Grant R01AG066710 and R01AG061188.?D.S.P.?is funded by?the Oncode Institute, which is partly financed by the Dutch Cancer Society.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/4/8
Y1 - 2022/4/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85127887311&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-29442-x
DO - 10.1038/s41467-022-29442-x
M3 - Article
C2 - 35395848
AN - SCOPUS:85127887311
SN - 2041-1723
VL - 13
SP - 1
EP - 16
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1923
ER -