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

• Main Authors: Altelaar, M. (Author), Altinok, S. (Author), Apriamashvili, G. (Author), Bleijerveld, O.B (Author), Boshuizen, J. (Author), D’Empaire Altimari, D. (Author), de Bruijn, B. (Author), Krijgsman, O. (Author), Ligtenberg, M.A (Author), Lin, C.-P (Author), Londino, J.D (Author), Oswalt, L.E (Author), Peeper, D.S (Author), Sanchez-Hodge, R. (Author), Schisler, J.C (Author), Traets, J.J.H (Author), van Vliet, A. (Author), Visser, N.L (Author), Vredevoogd, D.W (Author)
• Format: Article
• Language: English
• Published: Nature Research 2022
• Subjects: cell; degradation; enzyme activity; genetics; genome; human; Humans; metabolism; signal transduction; Signal Transduction; STUB1 protein, human; tumor; ubiquitin; Ubiquitin; ubiquitin protein ligase; ubiquitination; Ubiquitination; Ubiquitin-Protein Ligases
• Online Access: View Fulltext in Publisher
• ISBN: 20411723 (ISSN)
• DOI: 10.1038/s41467-022-29442-x

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).