Zdhhc5, a zinc-finger and aspartate-histidine-histidine-cysteine 5 protein, is a palmitoyl-acyltransferase (PAT) enzyme. Protein palmitoylation mediated by Zdhhc5 is involved in a wide range of cellular processes, including synaptic plasticity, cardiac function, cell adhesion, and fatty acid uptake [3]. It is mainly localized to the plasma membrane and has an extended cytoplasmic domain with regulatory features.

In various disease-related biological processes, Zdhhc5 has been shown to play crucial roles. In NLRP3 inflammasome-related innate immune response, Zdhhc5-mediated NLRP3 palmitoylation promotes NLRP3-NEK7 interaction and inflammasome activation. Silencing Zdhhc5 in human cells and Zdhhc5-/-mice blocks NLRP3 oligomerization, interaction with NEK7, and formation of large intracellular ASC aggregates, leading to the abrogation of caspase-1 activation, IL-1β/18 release, and GSDMD cleavage [1]. In glioma, knockdown of Zdhhc5 abrogates the S-palmitoylation and membrane distribution of FAK, impairing cell proliferation, invasion, and epithelial-mesenchymal transition (EMT) [2]. In non-apoptotic cell death, a catalytically active protein S-acyltransferase complex comprising Zdhhc5 and GOLGA7 is required for caspase-independent lethal 56 (CIL56)-induced non-apoptotic cell death [4].

In conclusion, Zdhhc5 is a key enzyme in protein palmitoylation, participating in multiple biological processes. The use of Zdhhc5 gene knockout (KO) mouse models, such as in the study of NLRP3 inflammasome-driven diseases, has revealed its significance in regulating innate immune responses and provided potential targets for treating related diseases. It also has implications in cancer-related processes like glioma development, highlighting its importance in disease-related research models.

References:

1. Zheng, Sihao, Que, Xiangyong, Wang, Shuxian, Zhang, Pingfeng, Pei, Huadong. 2023. ZDHHC5-mediated NLRP3 palmitoylation promotes NLRP3-NEK7 interaction and inflammasome activation. In Molecular cell, 83, 4570-4585.e7. doi:10.1016/j.molcel.2023.11.015. https://pubmed.ncbi.nlm.nih.gov/38092000/

2. Wang, Yang, Shen, Na, Yang, Yang, Yang, Ze, Wang, Zhangjie. 2024. ZDHHC5-mediated S-palmitoylation of FAK promotes its membrane localization and epithelial-mesenchymal transition in glioma. In Cell communication and signaling : CCS, 22, 46. doi:10.1186/s12964-023-01366-z. https://pubmed.ncbi.nlm.nih.gov/38233791/

3. Woodley, Keith T, Collins, Mark O. 2021. Regulation and function of the palmitoyl-acyltransferase ZDHHC5. In The FEBS journal, 288, 6623-6634. doi:10.1111/febs.15709. https://pubmed.ncbi.nlm.nih.gov/33415776/

4. Ko, Pin-Joe, Woodrow, Claire, Dubreuil, Michael M, Bassik, Michael C, Dixon, Scott J. 2019. A ZDHHC5-GOLGA7 Protein Acyltransferase Complex Promotes Nonapoptotic Cell Death. In Cell chemical biology, 26, 1716-1724.e9. doi:10.1016/j.chembiol.2019.09.014. https://pubmed.ncbi.nlm.nih.gov/31631010/