Pseudokinase STK40 promotes T<sub>H</sub>1 and T<sub>H</sub>17 cell differentiation by targeting FOXO transcription factors.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 39565845.
- Also identified by DOI 10.1126/sciadv.adp2919 and PMC identifier 11578171.
- Licence recorded as CC BY-NC.
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Abstract
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.
Medical subject headings
- Th17 Cells
- Th1 Cells
- Protein Serine-Threonine Kinases
- Cell Differentiation
- Encephalomyelitis, Autoimmune, Experimental
- Forkhead Box Protein O1