Palmitoyl-protein thioesterase-1 deficiency mediates the activation of the unfolded protein response and neuronal apoptosis in INCL
Palmitoyl-protein thioesterase-1 deficiency mediates the activation of the unfolded protein response and neuronal apoptosis in INCL
复制标题
DOI：
10.1093/hmg/ddi451
复制
发表时间：
2006-01-15
影响因子：
3.5
通讯作者：
Mukherjee, AB
中科院分区：
文献类型：
--
作者：
Zhang, ZJ;Lee, YC;Mukherjee, AB
许多蛋白质被棕榈酸修饰(S酰化)，其生物学功能包括信号转导、囊泡运输和维持细胞结构。虽然棕榈酰化是一种基本的修饰，但这些蛋白质也必须经历脱醛化，才能被溶酶体蛋白酶降解。棕榈酰基蛋白硫酯酶-1是一种溶酶体酶，它能裂解S酰化蛋白中的硫酯键，并去除棕榈酸酯残基，促进这些蛋白的降解。因此，PPT1基因的失活突变会导致婴儿神经元蜡样脂褐素沉着症(INCL)，这是一种儿童时期毁灭性的神经退行性储存障碍。尽管快速进行性脑萎缩是INCL最显著的病理表现，但其分子机制(S)仍不清楚。利用PPT1基因敲除小鼠(PPT1-KO)模拟人类INCL，我们在这里报告了这些小鼠脑细胞内质网(ER)的结构异常。此外，我们证明了生长相关蛋白-43(GAP-43)，一种棕榈酰化的神经元蛋白，在PPT1-KO小鼠的大脑中水平升高。此外，在PPT1缺陷的细胞中强制表达GAP-43会导致该蛋白在内质网中异常积聚。与这些结果一致，我们发现了激活未折叠蛋白反应(UPR)的证据，其标志是磷酸化翻译起始因子eIF2α水平的升高，伴侣蛋白如葡萄糖调节蛋白-78的表达增加，以及内质网中的半胱氨酸蛋白酶caspase-12的激活，介导caspase-3的激活和凋亡。我们的结果首次将PPT1缺乏与INCL中UPR的激活、细胞凋亡和神经变性联系起来，并确定了对这种一致致命疾病进行治疗干预的潜在靶点。
Numerous proteins undergo modification by palmitic acid (S-acylation) for their biological functions including signal transduction, vesicular transport and maintenance of cellular architecture. Although palmitoylation is an essential modification, these proteins must also undergo depalmitoylation for their degradation by lysosomal proteases. Palmitoyl-protein thioesterase-1 (PPT1), a lysosomal enzyme, cleaves thioester linkages in S-acylated proteins and removes palmitate residues facilitating the degradation of these proteins. Thus, inactivating mutations in the PPT1 gene cause infantile neuronal ceroid lipofuscinosis (INCL), a devastating neurodegenerative storage disorder of childhood. Although rapidly progressing brain atrophy is the most dramatic pathological manifestation of INCL, the molecular mechanism(s) remains unclear. Using PPT1-knockout (PPT1-KO) mice that mimic human INCL, we report here that the endoplasmic reticulum (ER) in the brain cells of these mice is structurally abnormal. Further, we demonstrate that the level of growth-associated protein-43 (GAP-43), a palmitoylated neuronal protein, is elevated in the brains of PPT1-KO mice. Moreover, forced expression of GAP-43 in PPT1-deficient cells results in the abnormal accumulation of this protein in the ER. Consistent with these results, we found evidence for the activation of unfolded protein response (UPR) marked by elevated levels of phosphorylated translation initiation factor, eIF2 alpha, increased expression of chaperone proteins such as glucose-regulated protein-78 and activation of caspase-12, a cysteine proteinase in the ER, mediating caspase-3 activation and apoptosis. Our results, for the first time, link PPT1 deficiency with the activation of UPR, apoptosis and neurodegeneration in INCL and identify potential targets for therapeutic intervention in this uniformly fatal disease.