Department of Medical Genetics and Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada.
Prog Neurobiol. 2012 May;97(2):220-38. doi: 10.1016/j.pneurobio.2011.11.002. Epub 2011 Dec 7.
Post-translational modification of proteins by the lipid palmitate is critical for protein localization and function. Palmitoylation is regulated by the opposing enzymes palmitoyl acyltransferases (PATs) and acyl protein thioesterases, which add and remove palmitate from proteins, respectively. Palmitoylation is particularly important for a number of processes including neuronal development and synaptic activity in the central nervous system. Dysregulated palmitoylation contributes to neuropsychiatric disease. In total six PATs (HIP14, HIP14L, ZDHHC8, ZDHHC9, ZDHHC12, and ZDHHC15) and one thioesterase (PPT1) have been implicated in Huntington disease (HD), Alzheimer disease, schizophrenia, mental retardation, and infantile and adult onset forms of neuronal ceroid lipofuscinosis. Currently there is no genetic link between PATs and Alzheimer disease pathogenesis but palmitoylation of amyloid precursor protein-processing enzyme, γ-secretase, influences β-amyloid generation. Several lines of evidence point to a role for palmitoylation by HIP14 in the pathogenesis of HD; HIP14 is dysfunctional in the presence of the HD mutation and Hip14-deficient mice develop features of HD. Wildtype huntingtin (the protein mutated in HD) enhances the PAT activity of HIP14 and mutant HTT interacts less with HIP14. Therefore, it may be that loss of the positive modulation of HIP14 activity due to reduced interaction with huntingtin is important in the disease mechanism. Preliminary evidence suggests a closely related PAT to HIP14, HIP14L, may also play a role in the pathogenesis of HD. In order to design rational therapeutic approaches to restore palmitoylation in neuropsychiatric disease, it will be critical to better understand the relationships between PATs and thioesterases with their regulators and substrates.
蛋白质的翻译后修饰由脂质棕榈酸酯介导对于蛋白质的定位和功能至关重要。棕榈酰化由相反的酶棕榈酰基转移酶（PATs）和酰基蛋白硫酯酶调节，它们分别将棕榈酸添加到和从蛋白质上去除。棕榈酰化对于许多过程非常重要，包括神经元发育和中枢神经系统中的突触活动。失调的棕榈酰化导致神经精神疾病。总共有六种 PAT（HIP14、HIP14L、ZDHHC8、ZDHHC9、ZDHHC12 和 ZDHHC15）和一种硫酯酶（PPT1）与亨廷顿病（HD）、阿尔茨海默病、精神分裂症、智力迟钝以及婴儿和成人发病形式的神经元蜡样脂褐质沉积症有关。目前，PAT 与阿尔茨海默病发病机制之间没有遗传联系，但淀粉样前体蛋白加工酶γ-分泌酶的棕榈酰化会影响β-淀粉样生成。有几条证据表明 HIP14 在 HD 发病机制中起作用；在存在 HD 突变的情况下，HIP14 功能失调，Hip14 缺陷小鼠会发展出 HD 的特征。野生型亨廷顿蛋白（HD 突变的蛋白）增强了 HIP14 的 PAT 活性，而突变型 HTT 与 HIP14 的相互作用较少。因此，由于与亨廷顿蛋白的相互作用减少而导致 HIP14 活性的正向调节丧失可能在疾病机制中很重要。初步证据表明，与 HIP14 密切相关的 PAT HIP14L 也可能在 HD 的发病机制中发挥作用。为了设计合理的治疗方法来恢复神经精神疾病中的棕榈酰化，了解 PAT 和硫酯酶与其调节剂和底物之间的关系将至关重要。
