ZDHHC22, a member of the palmitoyl-transferase family, is involved in palmitoylation, a process crucial for regulating protein stability and protein-protein interactions [1,2,4,5,6,7]. Palmitoylation by ZDHHC22 impacts various biological processes and is associated with multiple disease-related pathways. Genetic models, such as gene knockout models, can provide insights into its specific functions.

In breast cancer, ZDHHC22 expression is lower in estrogen receptor (ER) negative breast cancer tissues and cell lines. Its promoter methylation may contribute to this lower expression. ZDHHC22 inhibits breast cancer cell proliferation in vitro and in vivo, through reducing mTOR stability via palmitoylation and decreasing AKT signaling pathway activation. Ectopic expression can restore tamoxifen sensitivity in MCF-7R cells [1].

In influenza A virus-infected cells, the viral protein NS1 triggers ZDHHC22 upregulation, though its absence doesn't affect the acylation of viral proteins M2 and HA [2].

In liver cancer, ZDHHC22 is one of the 16 differentially expressed genes related to immunotherapy identified by machine-learning algorithms [3].

In the context of CCN3 secretion, ZDHHC22-mediated palmitoylation at C241 in the CCN3 TSP1 domain is required for CCN3 secretion, and aberrant palmitoylation inhibits neuronal axon growth [4].

In gliomas, ZDHHC22 is aberrantly expressed and may act through the PI3K/AKT signaling pathway. Inhibition of ZDHHCs, including ZDHHC22, suppresses glioma-cell viability, autophagy, and promotes apoptosis and sensitivity to temozolomide chemotherapy, while also weakening microglial migration [5].

In Alzheimer's disease, ZDHHC22 was identified as a key palmitoylation-related gene with moderate diagnostic potential and associations with immune cell infiltration [6].

In the regulation of BK channels, ZDHHC22 controls the palmitoylation of the intracellular S0-S1 loop, which is essential for efficient cell surface expression of BK channels [7].

In cattle, a microdeletion in the PEG3 domain leads to increased ZDHHC22 expression in fetuses carrying the deletion [8].

In summary, ZDHHC22-mediated palmitoylation plays essential roles in multiple biological processes, including cell proliferation, protein secretion, and ion-channel regulation. Its dysregulation is associated with various diseases such as breast cancer, gliomas, and Alzheimer's disease. Research using genetic models, especially knockout models, could potentially further clarify its specific functions and provide a basis for targeted therapeutic strategies.

References:

1. Huang, Jiefeng, Li, Jie, Tang, Jun, Ren, Guosheng, Xiang, Tingxiu. 2022. ZDHHC22-mediated mTOR palmitoylation restrains breast cancer growth and endocrine therapy resistance. In International journal of biological sciences, 18, 2833-2850. doi:10.7150/ijbs.70544. https://pubmed.ncbi.nlm.nih.gov/35541896/

2. Gadalla, Mohamed Rasheed, Morrison, Eliot, Serebryakova, Marina V, Kordyukova, Larisa, Veit, Michael. 2021. NS1-mediated upregulation of ZDHHC22 acyltransferase in influenza a virus infected cells. In Cellular microbiology, 23, e13322. doi:10.1111/cmi.13322. https://pubmed.ncbi.nlm.nih.gov/33629465/

3. Chen, Junhong, Jin, Hengwei, Zhou, Hao, Hei, Xufei, Liu, Kai. 2023. Research into the characteristic molecules significantly affecting liver cancer immunotherapy. In Frontiers in immunology, 14, 1029427. doi:10.3389/fimmu.2023.1029427. https://pubmed.ncbi.nlm.nih.gov/36860864/

4. Kim, Yujin, Yang, Hayoung, Min, Jeong-Ki, Jang, Sung-Wuk, Shim, Sungbo. 2017. CCN3 secretion is regulated by palmitoylation via ZDHHC22. In Biochemical and biophysical research communications, 495, 2573-2578. doi:10.1016/j.bbrc.2017.12.128. https://pubmed.ncbi.nlm.nih.gov/29287726/

5. Tang, Feng, Yang, Chao, Li, Feng-Ping, Wang, Ze-Fen, Li, Zhi-Qiang. 2022. Palmitoyl transferases act as potential regulators of tumor-infiltrating immune cells and glioma progression. In Molecular therapy. Nucleic acids, 28, 716-731. doi:10.1016/j.omtn.2022.04.030. https://pubmed.ncbi.nlm.nih.gov/35664705/

6. Mao, Sanying, Zhao, Xiyao, Wang, Lei, Man, Yilong, Li, Kaiyuan. 2025. Palmitoylation-related gene ZDHHC22 as a potential diagnostic and immunomodulatory target in Alzheimer's disease: insights from machine learning analyses and WGCNA. In European journal of medical research, 30, 46. doi:10.1186/s40001-025-02277-0. https://pubmed.ncbi.nlm.nih.gov/39844282/

7. Tian, Lijun, McClafferty, Heather, Knaus, Hans-Guenther, Ruth, Peter, Shipston, Michael J. 2012. Distinct acyl protein transferases and thioesterases control surface expression of calcium-activated potassium channels. In The Journal of biological chemistry, 287, 14718-25. doi:10.1074/jbc.M111.335547. https://pubmed.ncbi.nlm.nih.gov/22399288/

8. Flisikowski, Krzysztof, Venhoranta, Heli, Bauersachs, Stefan, Andersson, Magnus, Schnieke, Angelika. 2012. Truncation of MIMT1 gene in the PEG3 domain leads to major changes in placental gene expression and stillbirth in cattle. In Biology of reproduction, 87, 140. doi:10.1095/biolreprod.112.104240. https://pubmed.ncbi.nlm.nih.gov/23100617/