Selective processing and metabolism of disease-causing mutant prion proteins.
Selective processing and metabolism of disease-causing mutant prion proteins.
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DOI：
10.1371/journal.ppat.1000479
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发表时间：
2009-06
期刊：
影响因子：
6.7
通讯作者：
Hegde RS
中科院分区：
文献类型：
--
作者：
Ashok A;Hegde RS
朊病毒病是由细胞朊病毒蛋白（PrPC）的异常代谢引起的致命性神经退行性疾病。在这些疾病的遗传形式中，假设球状C-末端结构域中的突变有利于自发产生错误折叠的PrP构象异构体（包括可传递的PrPSc形式），其触发导致神经元死亡的下游途径。因此，对这些疾病的机械理解需要认识识别和降解异常PrPs的质量控制途径。在这里，我们提出了比较分析的生物合成，贩运和代谢的一组遗传性疾病引起的朊蛋白突变体的C-末端结构域。使用定量成像和生物化学，我们确定了一个错误折叠的亚群，每个突变体PrP的特点是相对洗涤剂不溶性，难以接近细胞表面，和不完整的聚糖修饰。错误折叠的突变体PrPs群体既没有被ER质量控制途径识别，也没有被路由到ER相关的降解，尽管在ER中存在明显的错误折叠。相反，突变PrPs贩运到高尔基体，从那里错误折叠的亚群被选择性地贩运在酸性隔室降解。令人惊讶的是，选择性重新路由不仅依赖于一个突变的球状结构域，但在高度保守的非结构化的N-末端的一个额外的赖氨酸基序。这些结果定义了一个特定的贩运和降解途径共享的许多致病PrP突变体。由于酸性溶酶体环境已被牵连在促进转化的PrPC的PrPSc，我们确定了一个murides选择性运输途径，这间室可能提供了一个细胞生物学基础的自发产生的PrPSc在家族性朊病毒病。朊病毒病是由细胞朊病毒蛋白（PrPC）异常代谢引起的传染性致死性神经退行性疾病。传播因子是PrPSc，PrP的一种错误折叠形式（构象异构体），能够将PrPC转化为PrPSc。PrPSc可以在遗传性朊病毒疾病中由于从突变的PrP基因合成异常的PrP形式而从头产生。这种突变的PrP形式，类似于其他异常蛋白质，通常应该被各种细胞的“质量控制”（QC）途径破坏;然而，一些人类疾病是由于这些QC系统的最终破坏，通常是由于突变蛋白质的长时间轰击。因此，我们试图确定通常科普致病性错误折叠PrPs的特定途径。通过仔细跟踪细胞中这些突变型PrP的产生和周转，我们发现了一种细胞内QC途径，该途径选择性地将生化异常的PrP物质路由到溶酶体。由于溶酶体系统被认为是PrPC转化为PrPSc的一个位点，因此我们确定了一个多克隆选择性转运途径，这可能为家族性朊病毒病中PrPSc的自发产生提供细胞生物学基础。重要的是，这些发现表明，这种QC途径的最终变化或破坏可能有助于疾病进展。
Prion diseases are fatal neurodegenerative disorders caused by aberrant metabolism of the cellular prion protein (PrPC). In genetic forms of these diseases, mutations in the globular C-terminal domain are hypothesized to favor the spontaneous generation of misfolded PrP conformers (including the transmissible PrPSc form) that trigger downstream pathways leading to neuronal death. A mechanistic understanding of these diseases therefore requires knowledge of the quality control pathways that recognize and degrade aberrant PrPs. Here, we present comparative analyses of the biosynthesis, trafficking, and metabolism of a panel of genetic disease-causing prion protein mutants in the C-terminal domain. Using quantitative imaging and biochemistry, we identify a misfolded subpopulation of each mutant PrP characterized by relative detergent insolubility, inaccessibility to the cell surface, and incomplete glycan modifications. The misfolded populations of mutant PrPs were neither recognized by ER quality control pathways nor routed to ER-associated degradation despite demonstrable misfolding in the ER. Instead, mutant PrPs trafficked to the Golgi, from where the misfolded subpopulation was selectively trafficked for degradation in acidic compartments. Surprisingly, selective re-routing was dependent not only on a mutant globular domain, but on an additional lysine-based motif in the highly conserved unstructured N-terminus. These results define a specific trafficking and degradation pathway shared by many disease-causing PrP mutants. As the acidic lysosomal environment has been implicated in facilitating the conversion of PrPC to PrPSc, our identification of a mutant-selective trafficking pathway to this compartment may provide a cell biological basis for spontaneous generation of PrPSc in familial prion disease. Prion diseases are transmissible fatal neurodegenerative diseases caused by aberrant metabolism of the cellular prion protein (PrPC). The transmissible agent is PrPSc, a misfolded version (conformer) of PrP capable of converting PrPC into PrPSc. PrPSc can be generated de novo in inherited prion diseases due to synthesis of aberrant PrP forms from a mutated PrP gene. Such mutant PrP forms, analogous to other aberrant proteins, should typically be destroyed by various cellular ‘quality control’ (QC) pathways; however, several human diseases result from an eventual breakdown in these QC systems, often due to prolonged bombardment by mutant proteins. We have therefore sought to identify the specific pathways that normally cope with disease-causing misfolded PrPs. By carefully following the generation and turnover of these mutant PrPs in cells, we have discovered an intracellular QC pathway that selectively routes biochemically aberrant PrP species to lysosomes. As the lysosomal system has been implicated as a site for conversion of PrPC to PrPSc, our identification of a mutant-selective trafficking pathway to this compartment may provide a cell biological basis for spontaneous generation of PrPSc in familial prion disease. Importantly, these findings suggest that eventual changes or breakdown of this QC pathway may contribute to disease progression.
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影响因子：
6
作者：
Capellari, S;Parchi, P;Petersen, RB
通讯作者：
Petersen, RB
DOI：
10.1083/jcb.200804157
发表时间：
2008-07-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hegde RS;Kang SW
通讯作者：
Kang SW
影响因子：
4
作者：
Campana, V;Sarnataro, D;Zurzolo, C
通讯作者：
Zurzolo, C
影响因子：
4.8
作者：
Kiachopoulos, S;Bracher, A;Tatzelt, J
通讯作者：
Tatzelt, J
影响因子：
4.5
作者：
Gilch, S;Nunziante, M;Schätzl, HM
通讯作者：
Schätzl, HM