Zdhhc23-KO Mouse

Zdhhc23, short for zinc finger DHHC-type palmitoyltransferase 23, is a key enzyme involved in protein palmitoylation, a post-translational modification. Protein palmitoylation plays a crucial role in diverse cellular processes such as immune regulation, lipid metabolism, and ion channel regulation [1,2,7]. It is associated with pathways like phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling, which are involved in cell growth, survival, and metabolism [4].

In hepatocellular carcinoma, Zdhhc23 mediates the palmitoylation of PHF2, enhancing its ubiquitin-dependent degradation. This disrupts the PHF2-mediated suppression of SREBP1c, a master lipogenesis transcription factor, thus remodeling lipid metabolism [1]. In the large yellow croaker, silencing of LczDHHC23 led to increased pro-inflammatory cytokine expression and decreased anti-inflammatory cytokines, highlighting its anti-inflammatory role in macrophage immune regulation [2]. In a neuropathic cancer pain model, upregulation of Zdhhc23 in spinal cord dorsal horn astrocytes led to increased GFAP palmitoylation and secretion of inflammatory factors, contributing to pain development [3]. In gliomas, inhibition of Zdhhc23 suppressed glioma-cell viability, autophagy, and promoted apoptosis, as well as weakened microglial migration [4]. In a gastric cancer model, Zdhhc23 mediated T-bet palmitoylation and promoted its degradation, inhibiting Th1 cell polarization and CD8+ T cell killing effect [5]. In a mouse model of INCL, reduced Zdhhc23 levels affected the S-palmitoylation of APT1, leading to microglia proliferation and neuroinflammation [6]. Also, Zdhhc23 controls the palmitoylation of the intracellular S0-S1 loop of BK channels, essential for their efficient cell surface expression [7].

In summary, Zdhhc23 is essential in multiple biological processes through its role in protein palmitoylation. Its study using various in vivo models, such as mouse models of cancer, immune-related diseases, and neurodegenerative conditions, has revealed its significance in disease-related processes like tumorigenesis, immune response dysregulation, and neuropathic pain development. Understanding Zdhhc23 function provides insights into potential therapeutic targets for these diseases.

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. 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/

6. 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/

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/