Abstract
Atopic dermatitis (AD) is a T helper (Th)2-biased disease with elevated expression of Th2 cytokines that responds to Th2 signaling blockade. TRIM32 is an E3 ubiquitin ligase with innate antiviral activity. In our previous studies, we showed that Trim32 null mice developed Th2-biased skin inflammation in response to imiquimod and associated a low level of TRIM32 with AD. In this study, we provide evidence that TRIM32 deficiency contributes to enhanced Th2 cell differentiation in vitro. Analysis of TRIM32-associated proteins from public databases identified protein kinase C (PKC)ζ as a TRIM32-associated protein that contributes to the regulation of Th2 signaling. We demonstrated that PKCζ was specifically ubiquitinated by TRIM32 and, further, that PKCζ stability tended to be increased in Th2 cells with a Trim32 null background. Furthermore, Prkcz null mice showed compromised AD-like phenotypes in the MC903 AD model. Consistently, a high PKCζ and low TRIM32 ratio was associated with CD4+ cells in AD human skin compared with those in healthy controls. Taken together, these findings suggest that TRIM32 functions as a regulator of PKCζ that controls the differentiation of Th2 cells important for AD pathogenesis.