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<p>Serine/threonine kinase 40 (STK40) belongs to the Tribbles family of pseudokinases, which serve as substrate adaptors for the CRL4<sup>COP1/DET1</sup> 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 <i>Stk40</i> 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 CRL4<sup>COP1/DET1</sup>-dependent proteasomal degradation. Collectively, our results identify the COP1/STK40 axis as a post-translational cell-intrinsic mechanism regulating T cell immunity.</p>

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

  • 期刊论文

  • 发表日期：

    2025年11月21日

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  • 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,
  • Mark S. Wilson,
  • Jill Schartner,
  • Soyoung A. Oh,
  • Kim Newton,
  • Vishva M. Dixit,
  • Sascha Rutz

摘要

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.