Zdhhc4, a zinc finger DHHC domain-containing palmitoyltransferase, is crucial for S-palmitoylation, a post-translational modification that adds a palmitoyl group to cysteine residues of target proteins. This modification is involved in various biological processes such as protein trafficking, stability, and signal transduction [1-10].

In a study on anti-PD-1 immunotherapy, mitochondrial CPT1A was found to recruit Zdhhc4 to catalyze MAVS Cys79-palmitoylation, which promotes MAVS stabilization and activation, enhancing antitumor immunity [1]. In pain research, Zdhhc4 physically interacts with TRPV1 and catalyzes its S-palmitoylation at specific cysteine residues, leading to TRPV1 degradation via the lysosome pathway and facilitating inflammatory pain relief [2]. In glioblastoma, Zdhhc4-mediated GSK3β palmitoylation at Cys14 residue enhances temozolomide resistance and glioblastoma stem cell self-renewal through the EZH2-STAT3 axis [3]. In metabolic dysfunction-associated steatohepatitis, Atf3 in macrophages increases Zdhhc4-mediated CD36 palmitoylation, which is involved in regulating the glucose-fatty acid cycle [4]. In lung adenocarcinoma, high expression of Zdhhc4 is associated with shorter overall survival, and its expression is related to tumor-infiltrating immune cells and immune checkpoint-related genes [5]. In CLN1 disease, Zdhhc4 is involved in the S-palmitoylation of NFATC4, which is important for regulating IP3R1-expression and lysosomal Ca++ homeostasis [6]. In SARS-CoV-2 research, overexpression of Zdhhc4 promotes the palmitoylation of the S protein, which is critical for S-mediated syncytia formation and virus entry [7]. Zdhhc4 also palmitoylates KAI1(CD82), which then inhibits angiogenesis through multiple mechanisms [8]. And in studies on the D2 dopamine receptor, Zdhhc4 was identified as an interacting protein, and its palmitoylation affects the receptor's trafficking and stability [9].

In conclusion, Zdhhc4 plays diverse and important roles in multiple biological processes and disease conditions, including cancer, pain regulation, metabolic diseases, neurodegenerative diseases, and viral infections. Research using various models has revealed its significance in protein palmitoylation-related pathways, providing potential therapeutic targets for these diseases.

References:

1. Zhang, Guiheng, Jiang, Peishan, Tang, Wen, Shi, Yang, Sheng, Wanqiang. 2023. CPT1A induction following epigenetic perturbation promotes MAVS palmitoylation and activation to potentiate antitumor immunity. In Molecular cell, 83, 4370-4385.e9. doi:10.1016/j.molcel.2023.10.043. https://pubmed.ncbi.nlm.nih.gov/38016475/

2. Zhang, Youjing, Zhang, Mengyu, Tang, Cheng, Li, Dongdong, Yao, Jing. 2024. Palmitoylation by ZDHHC4 inhibits TRPV1-mediated nociception. In EMBO reports, 26, 101-121. doi:10.1038/s44319-024-00317-0. https://pubmed.ncbi.nlm.nih.gov/39528731/

3. Zhao, Chenggang, Yu, Huihan, Fan, Xiaoqing, Fang, Zhiyou, Chen, Xueran. 2022. GSK3β palmitoylation mediated by ZDHHC4 promotes tumorigenicity of glioblastoma stem cells in temozolomide-resistant glioblastoma through the EZH2-STAT3 axis. In Oncogenesis, 11, 28. doi:10.1038/s41389-022-00402-w. https://pubmed.ncbi.nlm.nih.gov/35606353/

4. Hu, Shuwei, Li, Rui, Gong, Dongxu, Wu, Huijuan, Xu, Yanyong. 2024. Atf3-mediated metabolic reprogramming in hepatic macrophage orchestrates metabolic dysfunction-associated steatohepatitis. In Science advances, 10, eado3141. doi:10.1126/sciadv.ado3141. https://pubmed.ncbi.nlm.nih.gov/39047111/

5. Bian, Jing, Xiong, Wenji, Yang, Zhiguang, Zhang, Yanli, Liu, Chaoying. 2024. Identification and prognostic biomarkers among ZDHHC4/12/18/24, and APT2 in lung adenocarcinoma. In Scientific reports, 14, 522. doi:10.1038/s41598-024-51182-9. https://pubmed.ncbi.nlm.nih.gov/38177255/

6. Mondal, Avisek, Appu, Abhilash P, Sadhukhan, Tamal, Liu, Aiyi, Mukherjee, Anil B. 2022. Ppt1-deficiency dysregulates lysosomal Ca++ homeostasis contributing to pathogenesis in a mouse model of CLN1 disease. In Journal of inherited metabolic disease, 45, 635-656. doi:10.1002/jimd.12485. https://pubmed.ncbi.nlm.nih.gov/35150145/

7. Li, Daoqun, Liu, Yihan, Lu, Yue, Gao, Shan, Zhang, Leiliang. 2021. Palmitoylation of SARS-CoV-2 S protein is critical for S-mediated syncytia formation and virus entry. In Journal of medical virology, 94, 342-348. doi:10.1002/jmv.27339. https://pubmed.ncbi.nlm.nih.gov/34528721/

8. Lee, Jin-Woo, Hur, Jin, Kwon, Yoo-Wook, Baek, Sung Hee, Kim, Hyo-Soo. 2021. KAI1(CD82) is a key molecule to control angiogenesis and switch angiogenic milieu to quiescent state. In Journal of hematology & oncology, 14, 148. doi:10.1186/s13045-021-01147-6. https://pubmed.ncbi.nlm.nih.gov/34530889/

9. Ebersole, Brittany, Petko, Jessica, Woll, Matthew, Lüscher, Bernhard, Levenson, Robert. 2015. Effect of C-Terminal S-Palmitoylation on D2 Dopamine Receptor Trafficking and Stability. In PloS one, 10, e0140661. doi:10.1371/journal.pone.0140661. https://pubmed.ncbi.nlm.nih.gov/26535572/