Zdhhc19, a zinc finger Asp-His-His-Cys (ZDHHC)-family palmitoyl S-acyltransferase, is crucial for protein S-palmitoylation, a post-translational modification. This modification is involved in diverse biological processes, and Zdhhc19's function may be studied through genetic models like gene knockout mouse models to understand its role in vivo [1,3-6].

In mice, Zdhhc19 knockout males are sterile. Although spermatogenesis may not be disrupted, Zdhhc19-deficient spermatozoa have multiple defects including abnormal morphology, decreased motility, and disturbed acrosome reaction, making them unable to fertilize oocytes [3]. ZDHHC19 localizes to the cell membrane of step 4-9 spermatids in the mouse testis and promotes membrane stability in male germ cells. Its knockout leads to decreased testicular weight ratio, sperm number and motility, along with increased sperm abnormalities, mainly due to "folded" abnormal sperm from membrane fusion [1]. In cancer, ZDHHC19 is frequently amplified in multiple human cancers such as lung squamous cell carcinomas. It promotes STAT3 activation through S-palmitoylation, and its knockout in lung squamous cell carcinoma cells blocks STAT3 activity and inhibits fatty-acid-induced tumor-related phenotypes in vivo [2]. In autophagy, ZDHHC19 catalyzes the S-acylation of p62 (SQSTM1), which promotes p62 droplet recruitment into autophagosomes and efficient autophagic degradation of ubiquitinated proteins [4,5]. In osteosarcoma, ZDHHC19 is overexpressed, and its silencing inhibits tumor cell proliferation, invasion, and migration both in vitro and in vivo, with its pro-oncogenic effect mediated by activating the wnt/β-catenin pathway [6].

In summary, Zdhhc19 is essential for sperm functions in mice, plays a role in male germ cell membrane stability, and is involved in cancer-related STAT3 activation, autophagy regulation, and osteosarcoma progression. The study of Zdhhc19 using KO mouse models has provided valuable insights into its functions in male reproduction and disease conditions such as cancer and osteosarcoma.

References:

1. Wu, Yangyang, Zhang, Xin, Zhang, Xi, Huang, Xiaoyan, Liu, Mingxi. . ZDHHC19 localizes to the cell membrane of spermatids and is involved in spermatogenesis†. In Biology of reproduction, 106, 477-486. doi:10.1093/biolre/ioab224. https://pubmed.ncbi.nlm.nih.gov/34897408/

2. Niu, Jixiao, Sun, Yang, Chen, Baoen, Frank, David A, Wu, Xu. 2019. Fatty acids and cancer-amplified ZDHHC19 promote STAT3 activation through S-palmitoylation. In Nature, 573, 139-143. doi:10.1038/s41586-019-1511-x. https://pubmed.ncbi.nlm.nih.gov/31462771/

3. Wang, Shuai, Qiao, Hongjie, Wang, Pengxiang, Wang, Yuan, Qin, Danian. 2021. ZDHHC19 Is Dispensable for Spermatogenesis, but Is Essential for Sperm Functions in Mice. In International journal of molecular sciences, 22, . doi:10.3390/ijms22168894. https://pubmed.ncbi.nlm.nih.gov/34445597/

4. Huang, Xue, Yao, Jia, Liu, Lu, Tate, Edward W, Yang, Aimin. . S-acylation of p62 promotes p62 droplet recruitment into autophagosomes in mammalian autophagy. In Molecular cell, 83, 3485-3501.e11. doi:10.1016/j.molcel.2023.09.004. https://pubmed.ncbi.nlm.nih.gov/37802024/

5. Huang, Xue, Liu, Lu, Yao, Jia, Xiang, Tingxiu, Yang, Aimin. 2024. S-acylation regulates SQSTM1/p62-mediated selective autophagy. In Autophagy, 20, 1467-1469. doi:10.1080/15548627.2023.2297623. https://pubmed.ncbi.nlm.nih.gov/38124295/

6. Liang, Shuhong, Zhang, Xiaojian, Li, Jun. . Zinc finger Asp-His-His-Cys palmitoyl -acyltransferase 19 accelerates tumor progression through wnt/β-catenin pathway and is upregulated by miR-940 in osteosarcoma. In Bioengineered, 13, 7367-7379. doi:10.1080/21655979.2022.2040827. https://pubmed.ncbi.nlm.nih.gov/35297315/