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Article Abstract
Inappropriate CD4 T helper (T) cell differentiation leads to progression of inflammatory and autoimmune diseases, yet the regulatory mechanisms governing stability and activity of transcription factors controlling T cell differentiation remain elusive. Here, we describe how pseudokinase serine threonine kinase 40 (STK40) facilitates T1/T17 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 T1 and T17 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 T1/T17 cells. Together, our data suggest a crucial role of STK40 in T1 and T17 cell differentiation, thereby enabling better understanding of the molecular regulatory network of CD4 T cell differentiation and providing effective targets for the treatment of autoimmune diseases.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11578171 | PMC |
| http://dx.doi.org/10.1126/sciadv.adp2919 | DOI Listing |
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