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

Author

Listed:
  • 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
    University of Utrecht, and Netherlands Proteomics Center)

  • Daniel S. Peeper

    (The Netherlands Cancer Institute)

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.

Suggested Citation

  • 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 & Ale, 2022. "Ubiquitin ligase STUB1 destabilizes IFNγ-receptor complex to suppress tumor IFNγ signaling," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29442-x
    DOI: 10.1038/s41467-022-29442-x
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