Pseudokinase STK40 promotes T <sub>H</sub> 1 and T <sub>H</sub> 17 cell differentiation by targeting FOXO transcription factors
Inappropriate CD4<sup>+</sup> T helper (T<sub>H</sub>) cell differentiation leads to progression of inflammatory and autoimmune diseases, yet the regulatory mechanisms governing stability and activity of transcription factors controlling T<sub>H</sub> cell differentiation remain elusive. Here, we describe how pseudokinase serine threonine kinase 40 (STK40) facilitates T<sub>H</sub>1/T<sub>H</sub>17 differentiation under pathological conditions. STK40 in T cells is dispensable for immune homeostasis in resting mice. However, mice with T cell-specific deletion of STK40 exhibit attenuated symptoms of experimental autoimmune encephalomyelitis and colitis, accompanied by diminished T<sub>H</sub>1 and T<sub>H</sub>17 cell differentiation. Mechanistically, STK40 facilitates K48-linked polyubiquitination and proteasomal degradation of FOXO1/4 through promoting their interaction with E3 ligase COP1. Inhibition of FOXO4 or FOXO1, respectively, restores differentiation potential of STK40-deficient T<sub>H</sub>1/T<sub>H</sub>17 cells. Together, our data suggest a crucial role of STK40 in T<sub>H</sub>1 and T<sub>H</sub>17 cell differentiation, thereby enabling better understanding of the molecular regulatory network of CD4<sup>+</sup> T cell differentiation and providing effective targets for the treatment of autoimmune diseases.
Authors
- Zhenyan Jiang (ORCID: https://orcid.org/0000-0003-4594-7065)
- Hongrui Xiang
- Yuexiao Tao (ORCID: https://orcid.org/0000-0003-3820-0553)
- Bing Liao (ORCID: https://orcid.org/0000-0003-1279-1682)
- Huizi Wang (ORCID: https://orcid.org/0000-0002-3652-6210)
- Jia Li (ORCID: https://orcid.org/0000-0002-3606-3949)
- Chenyang Guan (ORCID: https://orcid.org/0009-0008-6422-7729)
- Ke He (ORCID: https://orcid.org/0000-0001-6446-9439)
- Xuefeng Wu (ORCID: https://orcid.org/0000-0002-6933-7280)
- Lina Wang (ORCID: https://orcid.org/0000-0003-1457-0015)
- Ting Zhang (ORCID: https://orcid.org/0000-0001-9391-8926)
- Dongyang Li (ORCID: https://orcid.org/0000-0003-0818-2526)
- Jing Hu (ORCID: https://orcid.org/0000-0001-5287-5181)
- Ying Jin (ORCID: https://orcid.org/0000-0001-9032-6255)
- Jiamin Liu (ORCID: https://orcid.org/0009-0007-9802-5562)
- Xin Li (ORCID: https://orcid.org/0009-0004-2983-3329)
- Wei Cao (ORCID: https://orcid.org/0000-0001-5628-7918)
- Jun Ni (ORCID: https://orcid.org/0009-0002-6105-9455)
Institutions
- Shanghai Jiao Tong University (CN)
- Ruijin Hospital (CN)
- Shanghai Institute of Nutrition and Health (CN)
- Tongren Hospital (CN)
- Institute of Immunology (HR)
- Shanghai Children's Hospital (CN)
Publication Details
- Journal
- Science Advances
- Published
- 2024-11-20
- DOI
- https://doi.org/10.1126/sciadv.adp2919
- Citations
- 3
- Primary Topic
- FOXO transcription factor regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.70
Funders
- National Natural Science Foundation of China
- Science and Technology Commission of Shanghai Municipality
- Shanghai Jiao Tong University
- School of Medicine, Shanghai Jiao Tong University
- National Key Research and Development Program of China
- Science and Technology Innovation Plan Of Shanghai Science and Technology Commission