Zdhhc14-KO Mouse

Zdhhc14, encoding zinc finger, DHHC-type containing 14 protein, is a palmitoyl acyltransferase (PAT) [1,2,3,5,7]. PATs are involved in S-acylation, a post-translational modification where fatty acids attach to cysteine residues, affecting protein stability, membrane association, and intracellular targeting [7]. Zdhhc14 may play crucial roles in normal physiological functions and is associated with multiple biological processes and disease states [7].

In the nervous system, knockdown of Zdhhc14 in rat hippocampal neurons reveals its role in controlling palmitoylation and axon initial segment (AIS) clustering of PSD93 and Kv1 potassium channels. This loss decreases outward currents and increases action potential firing in hippocampal neurons, highlighting its importance in neuronal excitability [1]. In cancer, inducible overexpression of Zdhhc14 leads to reduced cell viability and increased apoptosis in testicular germ cell tumours and prostate cancer through the classic caspase-dependent apoptotic pathway, while heterozygous knockout increases cell colony formation ability. Also, its overexpression inhibits tumourigenesis in a mouse xenograft model, suggesting it as a tumour suppressor [2]. However, in scirrhous type gastric cancer, overexpression of Zdhhc14 promotes migration and invasion, with knockdown decreasing cell invasiveness and downregulating MMP-17, integrins α5 and β1 [3]. In preeclampsia, siRNA-mediated knockdown of Zdhhc14 in trophoblast cell lines significantly inhibits cell proliferation and invasion [4]. In myocardial infarction, Zdhhc14 promotes gasdermin D (GSDMD) Cys192 palmitoylation, which aggravates cardiomyocyte pyroptosis [6].

In summary, Zdhhc14 has diverse functions. In the nervous system, it is involved in regulating neuronal excitability. In cancer, its role seems context-dependent, acting as a tumour suppressor in some cancers but promoting tumour progression in scirrhous type gastric cancer. In preeclampsia, it affects trophoblast cell function, and in myocardial infarction, it is related to cardiomyocyte pyroptosis. Studies using gene knockdown and overexpression models, though not all traditional KO/CKO mouse models, have provided valuable insights into Zdhhc14's functions in these disease areas.

References:

1. Sanders, Shaun S, Hernandez, Luiselys M, Soh, Heun, Tzingounis, Anastasios V, Thomas, Gareth M. 2020. The palmitoyl acyltransferase ZDHHC14 controls Kv1-family potassium channel clustering at the axon initial segment. In eLife, 9, . doi:10.7554/eLife.56058. https://pubmed.ncbi.nlm.nih.gov/33185190/

2. Yeste-Velasco, Marc, Mao, Xueying, Grose, Richard, Young, Bryan D, Lu, Yong-Jie. 2014. Identification of ZDHHC14 as a novel human tumour suppressor gene. In The Journal of pathology, 232, 566-77. doi:10.1002/path.4327. https://pubmed.ncbi.nlm.nih.gov/24407904/

3. Oo, Htoo Zarni, Sentani, Kazuhiro, Sakamoto, Naoya, Oue, Naohide, Yasui, Wataru. 2014. Overexpression of ZDHHC14 promotes migration and invasion of scirrhous type gastric cancer. In Oncology reports, 32, 403-10. doi:10.3892/or.2014.3166. https://pubmed.ncbi.nlm.nih.gov/24807047/

4. Zhu, Lisha, Lv, Ruitu, Kong, Lingchun, Li, Xiaotian. 2018. Reduced methylation downregulates CD39/ENTPD1 and ZDHHC14 to suppress trophoblast cell proliferation and invasion: Implications in preeclampsia. In Pregnancy hypertension, 14, 59-67. doi:10.1016/j.preghy.2018.03.012. https://pubmed.ncbi.nlm.nih.gov/30527120/

5. Yu, L, Reader, J C, Chen, C, Baer, M R, Ning, Y. 2010. Activation of a novel palmitoyltransferase ZDHHC14 in acute biphenotypic leukemia and subsets of acute myeloid leukemia. In Leukemia, 25, 367-71. doi:10.1038/leu.2010.271. https://pubmed.ncbi.nlm.nih.gov/21151021/

6. Zhuang, Zehao, Gu, Jianing, Li, B O, Yang, Ling. 2023. Inhibition of gasdermin D palmitoylation by disulfiram is crucial for the treatment of myocardial infarction. In Translational research : the journal of laboratory and clinical medicine, 264, 66-75. doi:10.1016/j.trsl.2023.09.007. https://pubmed.ncbi.nlm.nih.gov/37769810/

7. Greaves, Jennifer, Chamberlain, Luke H. . New links between S-acylation and cancer. In The Journal of pathology, 233, 4-6. doi:10.1002/path.4339. https://pubmed.ncbi.nlm.nih.gov/24615251/