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

Abstract

Inappropriate CD4⁺ T helper (T_H) cell differentiation leads to progression of inflammatory and autoimmune diseases, yet the regulatory mechanisms governing stability and activity of transcription factors controlling T_H cell differentiation remain elusive. Here, we describe how pseudokinase serine threonine kinase 40 (STK40) facilitates T_H1/T_H17 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_H1 and T_H17 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_H1/T_H17 cells. Together, our data suggest a crucial role of STK40 in T_H1 and T_H17 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.