Zdhhc17, a member of the zinc finger DHHC-domain containing (ZDHHC) family, is a S-acyltransferase that plays a crucial role in S-palmitoylation, an important post-translational modification [1]. This process is involved in various cellular functions, including protein trafficking, membrane association, and signal transduction, which are vital for normal physiological processes and are linked to multiple disease-related pathways [1,2,3,4,6,8,9]. Genetic models, such as knockout (KO) mice, can be valuable in studying Zdhhc17's functions.

In a high-fat diet-induced liver tumorigenesis model, Zdhhc17 was found to palmitoylate AKT, promoting its activation and thus contributing to the development of non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) [2]. In polycystic ovary syndrome (PCOS) research, ovarian ZDHHC17 expression was attenuated in patients, and its depletion in granulosa cells decreased HSP90α palmitoylation levels and hampered androgen-to-estrogen conversion [3]. In glioblastoma cells, Zdhhc17-mediated palmitoylation was indispensable for preserving Oct4A from lysosome degradation, maintaining its protein stability and the stem performance of glioma stem cells (GSCs) [4]. In zebrafish, loss-of-function of Zdhhc17 led to motor dysfunction due to a defect in axonal outgrowth of spinal motor neurons [5]. In swine acute diarrhea syndrome coronavirus (SADS-CoV) infection, genome-wide CRISPR knockout library screening in HeLa cells identified Zdhhc17 as an important host factor for the virus's infection, specifically required for its genomic RNA replication [7].

In conclusion, Zdhhc17 is essential for multiple biological processes, mainly through its role in S-palmitoylation. Studies using gene knockout models have revealed its involvement in diseases like liver cancer, PCOS, glioblastoma, and its potential as a drug target for SADS-CoV infection. These findings contribute to a better understanding of the pathophysiological mechanisms related to Zdhhc17 and may provide new strategies for disease treatment.

References:

1. Zhang, Ying, Fan, Sisi, He, Lu, Li, Lanfang. 2024. The ZDHHC13/ZDHHC17 subfamily: From biological functions to therapeutic targets of diseases. In Pharmacological research, 209, 107418. doi:10.1016/j.phrs.2024.107418. https://pubmed.ncbi.nlm.nih.gov/39306022/

2. Bu, Lang, Zhang, Zhengkun, Chen, Jianwen, Kuang, Ming, Guo, Jianping. 2024. High-fat diet promotes liver tumorigenesis via palmitoylation and activation of AKT. In Gut, 73, 1156-1168. doi:10.1136/gutjnl-2023-330826. https://pubmed.ncbi.nlm.nih.gov/38191266/

3. Zhao, Shanmeizi, Ma, Rujun, Jueraitetibaike, Kadiliya, Yao, Bing, Guo, Zhigang. 2023. ZDHHC17 participates in the pathogenesis of polycystic ovary syndrome by affecting androgen conversion to estrogen in granulosa cells. In Molecular and cellular endocrinology, 578, 112076. doi:10.1016/j.mce.2023.112076. https://pubmed.ncbi.nlm.nih.gov/37769867/

4. Chen, Xueran, Niu, Wanxiang, Fan, Xiaoqing, Yao, Xuebiao, Fang, Zhiyou. . Oct4A palmitoylation modulates tumorigenicity and stemness in human glioblastoma cells. In Neuro-oncology, 25, 82-96. doi:10.1093/neuonc/noac157. https://pubmed.ncbi.nlm.nih.gov/35727735/

5. Shi, Wei, Wang, Fen, Gao, Ming, Chen, Xueran, Hao, Aijun. 2015. ZDHHC17 promotes axon outgrowth by regulating TrkA-tubulin complex formation. In Molecular and cellular neurosciences, 68, 194-202. doi:10.1016/j.mcn.2015.07.005. https://pubmed.ncbi.nlm.nih.gov/26232532/

6. Voytyuk, Oleksandr, Ohata, Yae, Moustakas, Aristidis, Ten Dijke, Peter, Heldin, Carl-Henrik. 2024. Smad7 palmitoylation by the S-acyltransferase zDHHC17 enhances its inhibitory effect on TGF-β/Smad signaling. In The Journal of biological chemistry, 300, 107462. doi:10.1016/j.jbc.2024.107462. https://pubmed.ncbi.nlm.nih.gov/38876303/

7. Luo, Yun, Tan, Chee Wah, Xie, Shi-Zhe, Wang, Lin-Fa, Shi, Zheng-Li. 2021. Identification of ZDHHC17 as a Potential Drug Target for Swine Acute Diarrhea Syndrome Coronavirus Infection. In mBio, 12, e0234221. doi:10.1128/mBio.02342-21. https://pubmed.ncbi.nlm.nih.gov/34700373/

8. Butler, Liam, Locatelli, Carolina, Allagioti, Despoina, Salaun, Christine, Chamberlain, Luke H. 2022. S-acylation of Sprouty and SPRED proteins by the S-acyltransferase zDHHC17 involves a novel mode of enzyme-substrate interaction. In The Journal of biological chemistry, 299, 102754. doi:10.1016/j.jbc.2022.102754. https://pubmed.ncbi.nlm.nih.gov/36442513/

9. Lin, Jiatong, Lyu, Zejian, Feng, Huolun, Pan, Zihao, Li, Yong. 2024. CircPDIA3/miR-449a/XBP1 feedback loop curbs pyroptosis by inhibiting palmitoylation of the GSDME-C domain to induce chemoresistance of colorectal cancer. In Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy, 76, 101097. doi:10.1016/j.drup.2024.101097. https://pubmed.ncbi.nlm.nih.gov/38861804/