{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nZDHHC20 is a member of the DHHC (Asp‐His‐His‐Cys) family of integral membrane palmitoyltransferases that catalyze the reversible S‐acylation of proteins, thereby modulating their membrane affinity and function. Structural studies have shown that DHHC enzymes operate at the membrane–cytosol interface and can even deform the local lipid bilayer to enable access to fatty acyl–coenzyme A substrates, which is essential for their catalytic activity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn cancer cells, ZDHHC20-mediated palmitoylation plays a pivotal role in regulating oncogenic signaling. Inhibition of DHHC20 activity has been demonstrated to create a dependency on receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR), resulting in sustained receptor signaling and increased sensitivity to EGFR tyrosine kinase inhibitors. Moreover, overexpression of ZDHHC20 has been observed in several tumors and is associated with cellular transformation, suggesting that its palmitoylation activity can modulate growth-promoting signaling pathways."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "2", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its impact on growth factor signaling, ZDHHC20 is also crucial for immune cell function. Specifically, it catalyzes the S‐acylation of the ORAI1 calcium channel at residue Cys143—a modification that is essential for effective recruitment of ORAI1 to the T cell receptor (TCR) signaling complex. This palmitoylation event facilitates proper calcium flux and downstream signaling in T cells, thereby influencing immune responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nHigh-resolution crystallographic analyses combined with molecular dynamics simulations have further delineated the mechanism of ZDHHC20 action. These studies reveal that the enzyme binds palmitoyl–CoA through a hydrophobic pocket while engaging both the acyl chain and the CoA headgroup. This “bivalent” mode of binding not only ensures acyl chain-length selectivity but also optimizes autoacylation and subsequent substrate palmitoylation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRecent in vivo investigations have underscored the significance of ZDHHC20 in cancer metastasis and progression. In pancreatic ductal adenocarcinoma, for instance, ZDHHC20 has been identified as a key regulator of metastatic outgrowth by modulating the interaction between tumor cells and the innate immune system. Additionally, in KRAS-driven pancreatic cancer, overexpression of ZDHHC20 promotes tumor progression by inhibiting the chaperone-mediated autophagic degradation of YTHDF3, which leads to aberrant accumulation of the oncogene MYC. These findings position ZDHHC20 as a promising therapeutic target in malignancies where palmitoylation-dependent signaling is dysregulated."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Mitra S Rana, Pramod Kumar, Chul-Jin Lee, et al. 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