前颗粒蛋白通过溶酶体的酸化调节溶酶体功能和生物发生。,Human Molecular Genetics

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前颗粒蛋白通过溶酶体的酸化调节溶酶体功能和生物发生。
Human Molecular Genetics ( IF 3.1 ) Pub Date : 2017-01-12 , DOI: 10.1093/hmg/ddx011
Yoshinori Tanaka _{1,

2} , Genjiro Suzuki ₁ , Takashi Matsuwaki ₂ , Masato Hosokawa ₁ , Geidy Serrano ₃ , Thomas G Beach ₃ , Keitaro Yamanouchi ₂ , Masato Hasegawa ₁ , Masugi Nishihara ₂

Affiliation

PGRN基因功能丧失突变引起的前颗粒蛋白（PGRN）单倍体功能不足会导致额颞叶变性并伴有TDP-43积累，并且PGRN基因纯合突变的患者会出现神经元类固醇脂褐藻病。尽管仍不清楚为什么PGRN缺乏会引起神经退行性疾病，但越来越多的证据表明PGRN与溶酶体功能有关。在这里，我们显示PGRN是一种分泌型溶酶体蛋白，可通过控制溶酶体的酸化来调节溶酶体功能和生物发生。PGRN基因表达和蛋白质水平随溶酶体碱化剂或血清饥饿引起的溶酶体生物发生的增加而增加。PGRN的下调或功能不足导致溶酶体基因表达和蛋白质水平升高，而PGRN的过表达导致溶酶体基因表达和蛋白质水平降低。特别是，成熟组织蛋白酶D（CTSDmat）的水平根据PGRN的水平发生了巨大变化。在用PGRN转染的细胞中促进了溶酶体的酸化。然后，这导致组织蛋白酶B降解CTSDmat。分泌的PGRN通过sortilin或不依赖阳离子的甘露糖6-磷酸受体掺入细胞，并促进了溶酶体的酸化和CTSDmat的降解。此外，PGRN水平的变化导致不溶性TDP-43的细胞类型特异性增加。在PGRN缺乏的FTLD-TDP患者的脑组织中，CTSD和磷酸化的TDP-43积累在神经元中。

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Progranulin regulates lysosomal function and biogenesis through acidification of lysosomes.

Progranulin (PGRN) haploinsufficiency resulting from loss-of-function mutations in the PGRN gene causes frontotemporal lobar degeneration accompanied by TDP-43 accumulation, and patients with homozygous mutations in the PGRN gene present with neuronal ceroid lipofuscinosis. Although it remains unknown why PGRN deficiency causes neurodegenerative diseases, there is increasing evidence that PGRN is implicated in lysosomal functions. Here, we show PGRN is a secretory lysosomal protein that regulates lysosomal function and biogenesis by controlling the acidification of lysosomes. PGRN gene expression and protein levels increased concomitantly with the increase of lysosomal biogenesis induced by lysosome alkalizers or serum starvation. Down-regulation or insufficiency of PGRN led to the increased lysosomal gene expression and protein levels, while PGRN overexpression led to the decreased lysosomal gene expression and protein levels. In particular, the level of mature cathepsin D (CTSDmat) dramatically changed depending upon PGRN levels. The acidification of lysosomes was facilitated in cells transfected with PGRN. Then, this caused degradation of CTSDmat by cathepsin B. Secreted PGRN is incorporated into cells via sortilin or cation-independent mannose 6-phosphate receptor, and facilitated the acidification of lysosomes and degradation of CTSDmat. Moreover, the change of PGRN levels led to a cell-type-specific increase of insoluble TDP-43. In the brain tissue of FTLD-TDP patients with PGRN deficiency, CTSD and phosphorylated TDP-43 accumulated in neurons. Our study provides new insights into the physiological function of PGRN and the role of PGRN insufficiency in the pathogenesis of neurodegenerative diseases.

更新日期：2019-11-01

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