2. Academic Validation
  3. Ubiquitin ligase STUB1 destabilizes IFNγ-receptor complex to suppress tumor IFNγ signaling

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

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. d.peeper@nki.nl.
  • # 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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