Calcium-dependent protein acyltransferase DHHC21 controls activation of CD4+ T cells

Despite the recognized significance of reversible protein lipidation (S-acylation) for T cell receptor signal transduction, the enzymatic control of this post-translational modification in T cells remains poorly understood. Here, we demonstrate that DHHC21, a member of the DHHC family of mammalian protein acyltransferases, mediates agonist-induced S-acylation of proximal T cell signaling proteins. Using Zdhhc21dep mice expressing a functionally deficient version of DHHC21, we show that DHHC21 is a calcium/calmodulin-dependent enzyme critical for activation of naïve CD4+ T cells in response to T cell receptor stimulation. We found that disruption of the calcium/calmodulin binding domain of DHHC21 does not affect thymic T cell development but prevents differentiation of peripheral CD4+ T cells into Th1, Th2, and Th17 effector T helper lineages. Our findings identify DHHC21 as an essential component of the T cell receptor signaling machinery and define a new role for protein acyltransferases in regulation of T cell-mediated immunity. Significance This study identifies DHHC21, a member of the DHHC family of mammalian protein acyltransferases, as a novel component of the TCR signaling pathway and demonstrates that this enzyme critically regulates activation and differentiation of CD4+ T cells by mediating rapid TCR-induced S-acylation of signaling proteins. This finding shows that protein acyltransferases can play a vital function in regulation of T cell-mediated immunity and thus serve as potential drug targets in diseases associated with altered immune system homeostasis. ### Competing Interest Statement The authors have declared no competing interest.