ZDHHC21-driven S-palmitoylation of Themis regulates the function of T cells and maintains homeostatic balance

Palmitoylation is catalyzed by palmitoyl acyltransferases (PATs), which covalently attach palmitate to specific cysteine residues in substrate proteins [11,12].In mammals, known PATs mainly include 23 members of the zinc finger DHHC-type containing palmitoylase family, which are named because they all contain the conserved DHHC enzyme activity domain [13,14].Among these palmitoyl acyltransferases, ZDHHC21 has been identified as one of the few localized to the plasma membrane, enabling it to modulate cell surface receptor activity [15].Currently, numerous substrate proteins of ZDHHC21 have been identified: the Src family tyrosine kinase LCK and Fyn, AK2, fatty acid synthetase (FASN), PLC-1 and 1AR [5,[16][17][18][19][20]. From studies on ZDHHC21 in T cells, it has been shown that ZDHHC21 interacts with LCK and regulates LCK activation and downstream signaling required for T cell activation [8,21].A previous study suggests that ZDHHC2 serves as a protein acyltransferase for LCK [22].However, recent studies have also shown that ZDHHC21 knockdown impairs TCR signaling, reduces expression of T cell activation markers, and inhibits Th1 and Th2 differentiation [23,24].Despite of these findings, what ZDHHC21 substrates are in T cells and how it regulates TCR signaling and immune function have not been thoroughly investigated.In this study, using T cell-specific ZDHHC21 knockout mice that we generated, we demonstrated that ZDHHC21 plays a crucial role in optimal TCR signaling, T cell proliferation, and homeostasis.