Regulation of T cell receptor signaling by protein acyltransferase DHHC21

Abstract

S-acylationreversible post-translational lipidation of cysteine residuesis emerging as an important regulatory mechanism in T cell signaling. Dynamic S-acylation is critical for protein recruitment into the T cell receptor complex and initiation of the subsequent signaling cascade. However, the enzymatic control of protein S-acylation in T cells remains poorly understood. Here, we report a previously uncharacterized role of DHHC21, a member of the mammalian family of DHHC protein acyltransferases, in regulation of the T cell receptor pathway. We found that loss of DHHC21 prevented S-acylation of key T cell signaling proteins, resulting in disruption of the early signaling events and suppressed expression of T cell activation markers. Furthermore, downregulation of DHHC21 prevented activation and differentiation of naïve T cells into effector subtypes. Together, our study provides the first direct evidence that DHHC protein acyltransferases can play an essential role in regulation of T cell-mediated immunity.

Ca2+-dependent protein acyltransferase DHHC21 controls activation of CD4+ T cells

“…We next sought to examine the effect of the ΔF233 mutation on the acyltransferase activity of DHHC21. Previously, we detected direct stimulus-dependent interaction between DHHC21 and the Src-family kinase Lck (Fan et al, 2020). Furthermore, we showed that shRNAmediated downregulation of DHHC21 significantly decreased Sacylation of Lck and PLC-γ1 in resting EL4 lymphoma cells, suggesting that these proteins are direct targets of DHHC21 (Fan et al, 2020).…”

“…The transmembrane adaptor LAT has been reported to be dually S-acylated at cysteine residues located proximally to the inner face of the plasma membrane, and a selective defect in LAT S-acylation has been found to be associated with a state of T cell functional unresponsiveness known as T cell anergy (Hundt et al, 2006). Recently, a candidate-based screening of the proximal TCR signaling components allowed us to detect previously uncharacterized S-acylation of adaptor protein GRB2, PLC-γ1 and tyrosine kinase ZAP-70 (Fan et al, 2020;Tewari et al, 2021). A functional analysis of ZAP-70 S-acylation revealed that this modification is essential for ZAP-70 interaction with its protein substrates and subsequent transcriptional responses (Tewari et al, 2021).…”

“…S-acylation of the mammalian proteins is catalyzed by a family of 23 protein acyltransferases with a common DHHC (Asp-His-His-Cys) motif within the catalytic core and, typically, four transmembrane domains (Baekkeskov and Kanaani, 2009). In our previous studies, we identified a member of this family, DHHC21 (also known as ZDHHC21), as a protein acyltransferase mediating S-acylation of several proximal T cell signaling proteins (Fan et al, 2020). Downregulation of DHHC21 in EL4 mouse lymphoma cells resulted in their unresponsiveness to TCR stimulation, suggesting that DHHC21 can be a critical regulator of the T cell effector function (Fan et al, 2020).…”

“…In our previous studies, we identified a member of this family, DHHC21 (also known as ZDHHC21), as a protein acyltransferase mediating S-acylation of several proximal T cell signaling proteins (Fan et al, 2020). Downregulation of DHHC21 in EL4 mouse lymphoma cells resulted in their unresponsiveness to TCR stimulation, suggesting that DHHC21 can be a critical regulator of the T cell effector function (Fan et al, 2020). To evaluate the contribution of DHHC21 to T cellmediated immunity in an animal model, we used Zdhhc21 dep mice, which express a functionally deficient DHHC21 carrying an in-frame mutation resulting in a loss of a phenylalanine in position 233 (ΔF233) (Mayer et al, 1976;Mill et al, 2009).…”

T cell receptor–dependent S-acylation of ZAP-70 controls activation of T cells

“…Owing to their recent identification, little is known about the role of DHHC PATs in the regulation of the immune responses. Earlier, we identified DHHC21 as a PAT controlling T cell activation and differentiation of naive CD4 + T cells into T helper (Th) Th1 and Th2 subtypes ( 33 ). Downregulation of DHHC21 prevented S-acylation of Lck, Fyn, and LAT, suggesting that this enzyme could be involved in the regulation of proximal TCR signaling.…”