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

Abstract

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.SignificanceThis 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.

Regulation of Dynamic Protein S-Acylation

“…It is also worth noting that acyl-group exchange methods provide snapshot-like profiles of S-acylated proteins at a given time point. Our group and others used these methods over a time course to evaluate the dynamic S-acylation ( Chen et al, 2020 ; Shayahati et al, 2020 ).…”

“…We also found that the rapid palmitoylation of Lck following Fas stimulation is dependent on intracellular calcium levels. This is likely mediated by a calcium/calmodulin binding site in the C-terminal tail of DHHC21 ( Shayahati et al, 2020 ). Interestingly, we found that though APT1 deacylates Lck under resting conditions, it does not affect stimulus-dependent deacylation following Fas stimulation.…”

Regulation of T cell function by protein S-acylation

“…Recently, it has been found that S-acylation is required for the proper function of the immune system. For example, several key signaling T cell receptor proteins were identified as S-acylated, and this modification has been found to be critical for proper protein localization, function, and propagation of T cell receptor signaling in response to antigenic stimulation ( Tewari et al, 2021 ; Fan et al, 2020 ; Shayahati et al, 2021 ). Although a lot of progress has been made in the S-acylation field in the last decade, the full extent of S-acylation in T cells is still not fully understood or appreciated.…”