Ca2+-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 T cell receptor-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.

Dynamic S-acylation of STIM1 is required for store-operated Ca2+ entry

“…Future work will evaluate if Orai1 can also be S-acylated by DHHC21 and determine the DHHC enzyme(s) responsible for STIM1 S-acylation. Of note, we have shown dramatic defects in T cell function in DHHC21 mutant mice in vitro and in vivo which may be consistent with alterations in SOCE (25).…”

“…It has been shown that DHHC20 S-acylates Orai1 (12). We have shown that many TCR pathway components are S-acylated by the PM-localized DHHC21 (25-28). Future work will evaluate if Orai1 can also be S-acylated by DHHC21 and determine the DHHC enzyme(s) responsible for STIM1 S-acylation.…”

“…S-acylation of Orai1 is important for segregation of the channel to the immunological synapse (12). In our previous studies, we have shown that several TCR components are rapidly and transiently S-acylated during T cell activation to regulate immune responses (25-27,32). T cell signaling proteins such as Lck and ZAP70 are recruited into the immunological synapse, and we have shown that S-acylation is an important mechanism behind this recruitment and activation (26,28).…”

Dynamic S-acylation of the ER-resident protein stromal interaction molecule 1 (STIM1) is required for store-operated Ca2+ entry

“…We have shown that many TCR pathway components are S-acylated by the PM-localized DHHC21. We have shown that the DHHC21 binds to calcium/calmodulin ( 27 ). Mutation of the calcium/calmodulin site of DHHC21 in the depilated mouse leads to defects in T-cell activation and differentiation into its subsets establishing in vivo relevance ( 27 , 28 , 29 , 30 ).…”

“…We have shown that the DHHC21 binds to calcium/calmodulin ( 27 ). Mutation of the calcium/calmodulin site of DHHC21 in the depilated mouse leads to defects in T-cell activation and differentiation into its subsets establishing in vivo relevance ( 27 , 28 , 29 , 30 ). Future work will evaluate if Orai1 can also be S-acylated by DHHC21 and determine the DHHC enzyme(s) responsible for STIM1 S-acylation.…”