Zdhhc23-KO Mouse

Zdhhc23, also known as zinc finger DHHC-type palmitoyltransferase 23, is a crucial enzyme involved in protein palmitoylation. Protein palmitoylation is a post-translational modification where a palmitate group is attached to cysteine residues of proteins, regulating their function, localization, and stability. Zdhhc23-mediated palmitoylation is associated with multiple biological pathways and has overall significance in various physiological and pathological processes [1,2,3,4,5,6,7,8].

In hepatocellular carcinoma, Zdhhc23 mediates the palmitoylation of PHF2, enhancing its ubiquitin-dependent degradation. This disrupts the function of PHF2 as an E3 ubiquitin ligase of SREBP1c, a master lipogenesis transcription factor, leading to altered lipid metabolism [1].

In large yellow croaker, silencing Lczdhhc23 in macrophage/monocyte cells during Pseudomonas plecoglossicida infection increased pro-inflammatory cytokine expression, indicating its anti-inflammatory role through promoting M2-type macrophage polarization and macrophage necroptosis [2].

In a neuropathic cancer pain model, upregulated Zdhhc23 in spinal cord dorsal horn astrocytes led to increased palmitoylation of GFAP and secretion of inflammatory factors, contributing to cancer pain development [3].

In gliomas, inhibition of Zdhhc23 with 2-bromopalmitate suppressed glioma-cell viability, autophagy, and promoted apoptosis, also weakening microglial migratory ability [4].

In gastric cancer, Zdhhc23 mediated T-bet palmitoylation and promoted its degradation, inhibiting Th1 cell polarization and CD8+ T cell killing effect, while intervention could enhance anti-tumor immunity [6].

In a mouse model of INCL, reduced Zdhhc23 levels decreased membrane-bound APT1, increasing plasma membrane-localized H-Ras and stimulating microglia proliferation [8].

In conclusion, Zdhhc23 is essential in processes like lipid metabolism, immune regulation, pain development, and tumorigenesis. The study of Zdhhc23 using gene knockout or conditional knockout mouse models (or equivalent loss-of-function experiments in other systems) has revealed its role in these specific biological processes and disease conditions, providing insights into potential therapeutic targets for related diseases such as cancer, inflammation-related disorders, and neuropathic pain.

References:

1. Jeong, Do-Won, Park, Jong-Wan, Kim, Kyeong Seog, Fukuda, Junji, Chun, Yang-Sook. 2023. Palmitoylation-driven PHF2 ubiquitination remodels lipid metabolism through the SREBP1c axis in hepatocellular carcinoma. In Nature communications, 14, 6370. doi:10.1038/s41467-023-42170-0. https://pubmed.ncbi.nlm.nih.gov/37828054/

2. Dai, Ting, Zhao, Ziyue, Zhu, Tingfang, Nie, Li, Chen, Jiong. 2024. The anti-inflammatory role of zDHHC23 through the promotion of macrophage M2 polarization and macrophage necroptosis in large yellow croaker (Larimichthys crocea). In Frontiers in immunology, 15, 1401626. doi:10.3389/fimmu.2024.1401626. https://pubmed.ncbi.nlm.nih.gov/38868779/

3. Fan, Xiaoqing, Zhang, Siyu, Sun, Suling, Chen, Xueran, Fang, Zhiyou. 2024. GFAP palmitoylcation mediated by ZDHHC23 in spinal astrocytes contributes to the development of neuropathic pain. In Regional anesthesia and pain medicine, 49, 821-830. doi:10.1136/rapm-2023-104980. https://pubmed.ncbi.nlm.nih.gov/38050183/

4. 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/

5. Kong, Yue, Liu, Yugeng, Li, Xianzhe, Jiang, Zhenyou, Zhang, Qiang. 2023. Palmitoylation landscapes across human cancers reveal a role of palmitoylation in tumorigenesis. In Journal of translational medicine, 21, 826. doi:10.1186/s12967-023-04611-8. https://pubmed.ncbi.nlm.nih.gov/37978524/

6. Xin, Lin, Xu, He-Song, Fan, Luo-Jun, Gan, Jin-Heng, Liu, Jiang. . Methionine Restriction Exerts Anti-Tumor Immunity via Joint Intervention of T-Bet Palmitoylation in Gastric Cancer. In Biotechnology journal, 20, e202400574. doi:10.1002/biot.202400574. https://pubmed.ncbi.nlm.nih.gov/39989253/

7. Chen, Xueran, Hu, Lei, Yang, Haoran, Wang, Hongzhi, Fang, Zhiyou. 2019. DHHC protein family targets different subsets of glioma stem cells in specific niches. In Journal of experimental & clinical cancer research : CR, 38, 25. doi:10.1186/s13046-019-1033-2. https://pubmed.ncbi.nlm.nih.gov/30658672/

8. Sadhukhan, Tamal, Bagh, Maria B, Appu, Abhilash P, Liu, Aiyi, Mukherjee, Anil B. 2021. In a mouse model of INCL reduced S-palmitoylation of cytosolic thioesterase APT1 contributes to microglia proliferation and neuroinflammation. In Journal of inherited metabolic disease, 44, 1051-1069. doi:10.1002/jimd.12379. https://pubmed.ncbi.nlm.nih.gov/33739454/