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

  • Nat Commun. 2022 Apr 8;13(1):1923. doi: 10.1038/s41467-022-29442-x.
Georgi Apriamashvili   #  1 ,  David W Vredevoogd   #  1 ,  Oscar Krijgsman  1 ,  Onno B Bleijerveld  2 ,  Maarten A Ligtenberg  1 ,  Beaunelle de Bruijn  1 ,  Julia Boshuizen  1 ,  Joleen J H Traets  1 ,  Daniela D'Empaire Altimari  1 ,  Alex van Vliet  1 ,  Chun-Pu Lin  1 ,  Nils L Visser  1 ,  James D Londino  3 ,  Rebekah Sanchez-Hodge  4 ,  Leah E Oswalt  4 ,  Selin Altinok  4 ,  Jonathan C Schisler  4 ,  Maarten Altelaar  2  5 ,  Daniel S Peeper  6
Affiliations
  • 1. Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX, Amsterdam, The Netherlands.
  • 2. Proteomics Core Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX, Amsterdam, The Netherlands.
  • 3. Division of Pulmonary, Critical Care and Sleep Medicine, The Ohio State University Wexner Medical Center, 410 W 10th Avenue, Columbus, OH, USA.
  • 4. McAllister Heart Institute and Department of Pharmacology, The University of North Carolina at Chapel Hill, 111 Mason Farm Rd., 3340 C MBRB CB #7126, Chapel Hill, NC, USA.
  • 5. Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, and Netherlands Proteomics Center, Padualaan 8, 3584, CH, Utrecht, The Netherlands.
  • 6. Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX, Amsterdam, The Netherlands. [email protected].
  • # Contributed equally.
PMID: 35395848 DOI: 10.1038/s41467-022-29442-x
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.

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