Zdhhc13, a member of the zinc finger DHHC-domain containing (ZDHHC) family, is a palmitoyltransferase that mediates protein S-palmitoylation, an important post-translational modification. This process is involved in various cellular pathways such as autophagy, melanogenesis, and mitochondrial function, and is crucial for normal physiological processes [1-9]. Genetic models, especially mouse models, have been valuable in studying Zdhhc13's functions.

In autophagy, Zdhhc13 palmitoylates ULK1, enabling its translocation to the autophagosome formation site, which is critical for autophagy initiation [2]. In the context of melanogenesis, Zdhhc13-mediated palmitoylation of MC1R enhances its signaling, and AMPK-phosphorylated Zdhhc13 at S208 strengthens this effect, suppressing melanomagenesis [3,4,6]. In mice with Zdhhc13 deficiency, there are abnormal behaviors related to anxiety, motor function, and disrupted brain bioenergetics due to impaired Drp1 S-palmitoylation and mitochondrial dynamics [5]. In the skin, Zdhhc13's palmitoyl-acyl transferase activity is essential for skin barrier integrity, regulating the stability of proteins like PADi3 and TGM1 [8]. Also, Zdhhc13 deficiency in mice leads to abnormal liver function, lipid abnormalities, and hypermetabolism, with down-regulation of S-palmitoylation sites on proteins related to lipid metabolism and mitochondrial function [9].

In conclusion, Zdhhc13 is essential for multiple biological functions through its role in protein S-palmitoylation. Studies using Zdhhc13 knockout or conditional knockout mouse models have revealed its significance in diseases such as melanoma, Parkinson's disease, and those related to skin and liver function, providing insights into potential therapeutic targets for these conditions [1,7].