Human palmitoyl protein thioesterase: Evidence for lysosomal targeting of the enzyme and disturbed cellular routing in infantile neuronal ceroid lipofuscinosis
Human palmitoyl protein thioesterase: Evidence for lysosomal targeting of the enzyme and disturbed cellular routing in infantile neuronal ceroid lipofuscinosis
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DOI：
10.1002/j.1460-2075.1996.tb00909.x
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发表时间：
1996-10-01
期刊：
影响因子：
11.4
通讯作者：
Peltonen, L
中科院分区：
文献类型：
--
作者：
Hellsten, E;Vesa, J;Peltonen, L
棕榈酰蛋白硫酯酶（PPT）是一种在体外去除各种s酰化蛋白中棕榈酸残基的酶。我们最近在患有儿童神经退行性疾病的患者中发现了人类PPT基因的突变，婴儿神经性ceroid lipofuscinosis (INCL)，其显著表现局限于新皮质来源的神经元。在这里，我们在COS-1细胞中表达了人类PPT cDNA，并通过甘露糖6-磷酸受体介导的途径证明了酶的溶酶体靶向。该酶也被分泌到生长培养基中，并能被受体细胞内吞。我们进一步证明了携带世界上最常见的INCL突变Arg122Trp的PPT细胞内路径被干扰到溶酶体。结果表明INCL是一种新型的溶酶体酶缺乏症。此外，导致神经退行性疾病的PPT基因缺陷表明，尚未表征的PPT底物的去棕榈酰化对出生后发育或皮层神经元的维持至关重要。
Palmitoyl protein thioesterase (PPT) is an enzyme that removes palmitate residues from various S-acylated proteins in vitro. We recently identified mutations in the human PPT gene in patients suffering from a neurodegenerative disease in childhood, infantile neuronal ceroid lipofuscinosis (INCL), with dramatic manifestations limited to the neurons of neocortical origin, Here we have expressed the human PPT cDNA in COS-1 cells and demonstrate the lysosomal targeting of the enzyme via the mannose 6-phosphate receptor-mediated pathway. The enzyme was also secreted into the growth medium and could be endocytosed by recipient cells. We further demonstrate the disturbed intracellular routing of PPT carrying the worldwide most common INCL mutation, Arg122Trp, to lysosomes. The results provide evidence that INCL represents a novel lysosomal enzyme deficiency. Further, the defect in the PPT gene causing a neurodegenerative disorder suggests that depalmitoylation of the still uncharacterized substrate(s) for PPT is critical for postnatal development or maintenance of cortical neurons.