ZDHHC21, a zinc finger DHHC domain-containing protein palmitoyltransferase, plays a crucial role in protein palmitoylation, a process that modulates protein stability, function, and subcellular location. This palmitoylation process is involved in various biological pathways, influencing key cellular functions and overall biological importance. Genetic models, such as KO/CKO mouse models, have been instrumental in studying ZDHHC21's function [1,2,3,5,6].

In acute myeloid leukemia (AML), depletion or inhibition of ZDHHC21 in AML cells effectively induced myeloid differentiation and weakened stemness potential by inhibiting mitochondrial oxidative phosphorylation (OXPHOS). Mechanistically, ZDHHC21 specifically catalyzed the palmitoylation of mitochondrial adenylate kinase 2 (AK2) and activated OXPHOS. Inhibition of ZDHHC21 arrested AML cell growth in vivo and extended the survival of mice inoculated with AML cells, suggesting it as a promising therapeutic target for AML patients [1].

In Alzheimer's disease, a ZDHHC21 p.T209S mutation in a Han Chinese family was identified. ZDHHC21T209S/T209S knock-in mice exhibited cognitive impairment and synaptic dysfunction. The mutation enhanced FYN palmitoylation, over-activated NMDAR2B, and increased APP palmitoylation, contributing to Aβ production. Palmitoyltransferase inhibitors reversed synaptic function impairment, indicating aberrant protein palmitoylation mediated by ZDHHC21 mutations as a new pathogenic mechanism of AD [2].

In the context of depression, ZDHHC21 was identified as a major palmitoyl-acyltransferase for the serotonin 1A receptor (5-HT1AR). Depletion of ZDHHC21 in rodent models reduced 5-HT1AR palmitoylation and led to depression-like behaviors. In human post-mortem brain samples from MDD patients, ZDHHC21 expression and 5-HT1AR palmitoylation were reduced [3].

In the gut, pharmacological inhibition or genetic ablation of ZDHHC21 in mice attenuated burn-induced gut epithelial hyperpermeability, suggesting ZDHHC21 as a potential therapeutic target for burn-induced intestinal barrier dysfunction [4].

In vascular function, mice expressing non-functional ZDHHC21 (F233Δ) showed blunted responsiveness to phenylephrine, hypotension, and tachycardia. ZDHHC21 was shown to palmitoylate the α1D adrenoceptor, suggesting a role in regulating vascular tone and blood pressure [5].

In septic injury-induced renal dysfunction, DHHC21 deficiency in Zdhhc21dep/dep mice attenuated renal pathology, improved renal perfusion, and blunted the palmitoylation of vascular α1-adrenergic receptor (α1AR) and activation of its downstream effector ERK [6].

In conclusion, ZDHHC21 is essential for protein palmitoylation and is involved in multiple biological processes. Model-based research, especially through KO/CKO mouse models, has revealed its significance in diseases such as AML, Alzheimer's disease, depression, burn-induced gut dysfunction, and disorders related to vascular and renal function. Understanding ZDHHC21's function provides potential therapeutic targets for these disease areas.

References:

1. Shao, Xuejing, Xu, Aixiao, Du, Wenxin, He, Qiaojun, Ying, Meidan. . The palmitoyltransferase ZDHHC21 regulates oxidative phosphorylation to induce differentiation block and stemness in AML. In Blood, 142, 365-381. doi:10.1182/blood.2022019056. https://pubmed.ncbi.nlm.nih.gov/37216691/

2. Li, Wenwen, Pang, Yana, Wang, Yan, Jia, Longfei, Jia, Jianping. 2023. Aberrant palmitoylation caused by a ZDHHC21 mutation contributes to pathophysiology of Alzheimer's disease. In BMC medicine, 21, 223. doi:10.1186/s12916-023-02930-7. https://pubmed.ncbi.nlm.nih.gov/37365538/

3. Gorinski, Nataliya, Bijata, Monika, Prasad, Sonal, Pandey, Ghanshyam, Ponimaskin, Evgeni. 2019. Attenuated palmitoylation of serotonin receptor 5-HT1A affects receptor function and contributes to depression-like behaviors. In Nature communications, 10, 3924. doi:10.1038/s41467-019-11876-5. https://pubmed.ncbi.nlm.nih.gov/31477731/

4. Haines, R J, Wang, C Y, Yang, C G Y, Wang, F, Wu, M H. 2017. Targeting palmitoyl acyltransferase ZDHHC21 improves gut epithelial barrier dysfunction resulting from burn-induced systemic inflammation. In American journal of physiology. Gastrointestinal and liver physiology, 313, G549-G557. doi:10.1152/ajpgi.00145.2017. https://pubmed.ncbi.nlm.nih.gov/28838985/

5. Marin, Ethan P, Jozsef, Levente, Di Lorenzo, Annarita, Velazquez, Heino, Sessa, William C. 2015. The Protein Acyl Transferase ZDHHC21 Modulates α1 Adrenergic Receptor Function and Regulates Hemodynamics. In Arteriosclerosis, thrombosis, and vascular biology, 36, 370-9. doi:10.1161/ATVBAHA.115.306942. https://pubmed.ncbi.nlm.nih.gov/26715683/

6. Yang, Xiaoyuan, Zheng, Ethan, Ma, Yonggang, Wu, Mack H, Yuan, Sarah Y. 2021. DHHC21 deficiency attenuates renal dysfunction during septic injury. In Scientific reports, 11, 11146. doi:10.1038/s41598-021-89983-x. https://pubmed.ncbi.nlm.nih.gov/34045489/