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2025

Nat Immunol . 2025 Dec;26(12):2270-2279. doi: 10.1038/s41590-025-02333-1. Epub 2025 Nov 21.

Pseudokinase STK40 limits T cell exhaustion through COP1-dependent degradation of AP1-family transcription factors

Svetlana Altshuler-Keylin, Nicole Caduff, Isabel E Ishizuka, Rohit Reja, Katherine Nutsch, Chan Gao, Joy Wang, Ulrike Kaufmann, Mayra Cruz Tleugabulova, Elizabeth Dixon, Hannah Little-Hooy, Rachana Pradhan, Rosa Barreira da Silva, Teresita L Arenzana, Min Xu 5, Mark S Wilson, Jill Schartner, Soyoung A Oh, Kim Newton, Vishva M Dixit, Sascha Rutz

Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA. Department of Research Oncology, Genentech, South San Francisco, CA, USA. Department of Computational Sciences, Genentech, South San Francisco, CA, USA. Department of Translational Oncology, Genentech, South San Francisco, CA, USA. Department of Translational Immunology, Genentech, South San Francisco, CA, USA. Department of Immunology, Genentech, South San Francisco, CA, USA. Biogen, South San Francisco, CA, USA. Department of Inflammation, Amgen, South San Francisco, CA, USA. Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA. Department of Research Oncology, Genentech, South San Francisco, CA, USA. Department of Inflammation, Gilead Sciences, Foster City, CA, USA.

Service type: Knock-in mice

Abstract

Serine/threonine kinase 40 (STK40) belongs to the Tribbles family of pseudokinases, which serve as substrate adaptors for the CRL4COP1/DET1 E3 ubiquitin ligase complex. Tribbles-1 and Tribbles-2 promote the degradation of CCAAT/enhancer-binding protein (C/EBP) transcription factors in hematopoietic cells. STK40 also regulates C/EBP proteins, and although some immune system functions have recently emerged, its specific role in cytotoxic T cell responses has not been characterized. Here we show that murine STK40 restricts homeostatic and antigen-driven T cell expansion. During chronic viral infection, T cell-specific deletion of Stk40 improved viral clearance and reduced the proportion of terminally exhausted antigen-specific T cells. STK40-deficient T cells exhibited increased expression of markers of cell proliferation and AP-1 target genes. Biochemically, STK40 interacted with the AP-1 transcription factor c-Jun, and was required for its CRL4COP1/DET1-dependent proteasomal degradation. Collectively, our results identify the COP1/STK40 axis as a post-translational cell-intrinsic mechanism regulating T cell immunity.

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