Prions amplify through degradation of the VPS10P sorting receptor sortilin.
Prions amplify through degradation of the VPS10P sorting receptor sortilin.
复制标题
DOI：
10.1371/journal.ppat.1006470
复制
发表时间：
2017-06
期刊：
影响因子：
6.7
通讯作者：
Sakaguchi S
中科院分区：
文献类型：
--
作者：
Uchiyama K;Tomita M;Yano M;Chida J;Hara H;Das NR;Nykjaer A;Sakaguchi S
朊病毒病是一组由朊病毒引起的致命神经退行性疾病，主要由异常折叠的朊病毒蛋白亚型PrPSc组成。朊病毒疾病的关键致病事件是朊病毒或PrPSc通过细胞朊病毒蛋白PrPC向PrPSc的组成型构象转化在脑中进行性积累。然而，PrPSc在朊病毒感染的神经元中逐渐积累的细胞机制仍然未知。在这里，我们表明，PrPSc是逐步积累在朊病毒感染的细胞通过降解的VPS 10 P分选受体分拣蛋白。我们首先表明，分拣蛋白与PrPC和PrPSc相互作用，并将它们分类到溶酶体进行降解。一致地，分拣蛋白敲低增加朊病毒感染细胞中PrPSc的积累。相反，分拣蛋白的过度表达减少朊病毒感染细胞中PrPSc的积累。这些结果表明，分拣蛋白负调控朊病毒感染的细胞中PrPSc的积累。分拣蛋白在PrPSc积累中的负面作用在感染朊病毒的分拣蛋白敲除小鼠中得到进一步证实。受感染的小鼠加速了朊病毒疾病，PrPSc在它们的大脑中早期积累。有趣的是，分拣蛋白在感染朊病毒的细胞和小鼠大脑中减少。用溶酶体抑制剂而不是蛋白酶体抑制剂处理朊病毒感染的细胞，增加了分拣蛋白的水平。此外，分拣蛋白减少后，PrPSc成为感染朊病毒后在细胞中检测。这些结果表明PrPSc积累刺激溶酶体中分拣蛋白降解。综上所述，这些结果表明，PrPSc积累本身可能会损害分拣蛋白介导的分选PrPC和PrPSc的溶酶体降解的分拣蛋白刺激溶酶体的分拣蛋白，最终导致朊病毒感染的细胞中的PrPSc进行性积累。一旦主要由PrPSc组成的朊病毒感染宿主，它们就会在宿主的大脑中组成性繁殖。通过PrPC向PrPSc的组成型构象转化，PrPSc的逐步产生是朊病毒繁殖的基础。然而，使朊病毒感染的细胞中的PrPSc的逐步生产的机制仍然未知。我们在这里发现，VPS 10 P分选受体分拣蛋白通过与PrPC和PrPSc结合并随后将它们运输到溶酶体蛋白降解途径而参与感染细胞中PrPC和PrPSc的降解。有趣的是，我们还发现，在朊病毒感染的细胞中，分拣蛋白的降解在溶酶体中受到刺激，这可能是分拣蛋白-PrPC或-PrPSc复合物被运输到溶酶体的结果。我们的研究结果表明，PrPSc本身损害分拣蛋白介导的降解PrPC和PrPSc通过刺激溶酶体中分拣蛋白的降解。通过增加PrPC转化为PrPSc的机会和积累已经产生的PrPSc，最终导致朊病毒感染细胞中PrPSc的逐步产生。这种机制在感染朊病毒的分拣蛋白-KO小鼠中得到证实。这些小鼠的朊病毒疾病随着PrPSc在其大脑中的早期积累而加剧。
Prion diseases are a group of fatal neurodegenerative disorders caused by prions, which consist mainly of the abnormally folded isoform of prion protein, PrPSc. A pivotal pathogenic event in prion disease is progressive accumulation of prions, or PrPSc, in brains through constitutive conformational conversion of the cellular prion protein, PrPC, into PrPSc. However, the cellular mechanism by which PrPSc is progressively accumulated in prion-infected neurons remains unknown. Here, we show that PrPSc is progressively accumulated in prion-infected cells through degradation of the VPS10P sorting receptor sortilin. We first show that sortilin interacts with PrPC and PrPSc and sorts them to lysosomes for degradation. Consistently, sortilin-knockdown increased PrPSc accumulation in prion-infected cells. In contrast, overexpression of sortilin reduced PrPSc accumulation in prion-infected cells. These results indicate that sortilin negatively regulates PrPSc accumulation in prion-infected cells. The negative role of sortilin in PrPSc accumulation was further confirmed in sortilin-knockout mice infected with prions. The infected mice had accelerated prion disease with early accumulation of PrPSc in their brains. Interestingly, sortilin was reduced in prion-infected cells and mouse brains. Treatment of prion-infected cells with lysosomal inhibitors, but not proteasomal inhibitors, increased the levels of sortilin. Moreover, sortilin was reduced following PrPSc becoming detectable in cells after infection with prions. These results indicate that PrPSc accumulation stimulates sortilin degradation in lysosomes. Taken together, these results show that PrPSc accumulation of itself could impair the sortilin-mediated sorting of PrPC and PrPSc to lysosomes for degradation by stimulating lysosomal degradation of sortilin, eventually leading to progressive accumulation of PrPSc in prion-infected cells. Once prions consisting mainly of PrPSc infect hosts, they constitutively propagate in their brains. Progressive production of PrPSc through the constitutive conformational conversion of PrPC into PrPSc underlies prion propagation. However, the mechanism enabling progressive production of PrPSc in prion-infected cells remains unknown. We here found that the VPS10P sorting receptor sortilin is involved in degradation of PrPC and PrPSc in infected cells by binding to both molecules and subsequently trafficking them to the lysosomal protein degradation pathway. Interestingly, we also found that degradation of sortilin was stimulated in lysosomes in prion-infected cells possibly as a result of the sortilin-PrPC or -PrPSc complexes being trafficked to lysosomes. Our findings indicate that PrPSc itself impairs the sortilin-mediated degradation of PrPC and PrPSc by stimulating degradation of sortilin in lysosomes. This eventually results in progressive production of PrPSc in prion-infected cells by increasing the opportunity of PrPC to convert into PrPSc and by accumulating the already produced PrPSc. This mechanism was confirmed in sortilin-KO mice infected with prions. The mice had exacerbated prion disease with earlier accumulation of PrPSc in their brains.
登录
查看更多内容
影响因子：
6.8
作者：
Reitz C;Tosto G;Vardarajan B;Rogaeva E;Ghani M;Rogers RS;Conrad C;Haines JL;Pericak-Vance MA;Fallin MD;Foroud T;Farrer LA;Schellenberg GD;George-Hyslop PS;Mayeux R;Alzheimer's Disease Genetics Consortium (ADGC)
通讯作者：
Alzheimer's Disease Genetics Consortium (ADGC)
影响因子：
4.8
作者：
Finan, Gina M.;Okada, Hirokazu;Kim, Tae-Wan
通讯作者：
Kim, Tae-Wan
影响因子：
11.4
作者：
Sunyach, C;Jen, A;Morris, R
通讯作者：
Morris, R
影响因子：
16.2
作者：
Hu, Fenghua;Padukkavidana, Thihan;Vaegter, Christian B.;Brady, Owen A.;Zheng, Yanqiu;Mackenzie, Ian R.;Feldman, Howard H.;Nykjaer, Anders;Strittmatter, Stephen M.
通讯作者：
Strittmatter, Stephen M.
影响因子：
4.8
作者：
CHEN, SG;TEPLOW, DB;AUTILIOGAMBETTI, L
通讯作者：
AUTILIOGAMBETTI, L