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Pseudokinase STK40 promotes TH1 and TH17 cell differentiation by targeting FOXO transcription factors

Yuexiao Tao1, Zhenyan Jiang1, Huizi Wang1

  • 1Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Shanghai Jiao Tong University School of Medicine; Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine; and Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Science Advances
|November 20, 2024
PubMed

Insights

Pseudokinase STK40 promotes T helper 1/17 cell differentiation in autoimmune diseases by degrading FOXO1/4. Inhibiting STK40 may offer new treatments for inflammatory and autoimmune conditions.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • Dysregulated CD4+ T helper cell differentiation drives inflammatory and autoimmune diseases.
  • Mechanisms controlling T helper cell transcription factor stability are not fully understood.

Purpose of the Study:

  • To investigate the role of pseudokinase STK40 in T helper 1 (TH1) and T helper 17 (TH17) cell differentiation.
  • To elucidate the molecular mechanisms by which STK40 regulates T helper cell differentiation under pathological conditions.

Main Methods:

  • T cell-specific STK40 deletion in mice.
  • Assessment of experimental autoimmune encephalomyelitis and colitis models.
  • Analysis of TH1/TH17 cell differentiation.
  • Investigation of STK40's interaction with FOXO1/4 and COP1 via ubiquitination assays.

Main Results:

  • STK40 is dispensable for immune homeostasis in resting mice but crucial for TH1/TH17 differentiation in disease.
  • Mice lacking T cell STK40 showed reduced experimental autoimmune encephalomyelitis and colitis severity.
  • STK40 promotes TH1/TH17 differentiation by mediating K48-linked polyubiquitination and degradation of FOXO1/4 via COP1.
  • Inhibition of FOXO1/4 rescued TH1/TH17 differentiation in STK40-deficient cells.

Conclusions:

  • STK40 plays a critical role in pathological TH1 and TH17 cell differentiation.
  • STK40 acts by promoting FOXO1/4 degradation, linking it to autoimmune disease progression.
  • STK40 represents a potential therapeutic target for autoimmune diseases.

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