Disease-associated mutant ubiquitin causes proteasomal impairment and enhances the toxicity of protein aggregates.
Disease-associated mutant ubiquitin causes proteasomal impairment and enhances the toxicity of protein aggregates.
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DOI：
10.1371/journal.pgen.1000382
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发表时间：
2009-02
期刊：
影响因子：
4.5
通讯作者：
True HL
中科院分区：
文献类型：
--
作者：
Tank EM;True HL
蛋白质稳态对细胞存活至关重要，其失调与阿尔茨海默病（AD）和其他神经退行性疾病有关。尽管越来越多的赞赏涉及家族形式的AD的致病机制，少得多是已知的散发病例。在家族性和散发性AD中发现的聚集体通常包括与疾病通常相关的蛋白质以外的蛋白质。一种这样的蛋白质是泛素的突变形式，UBB+1，一种由野生型泛素基因的分子误读产生的移码产物。UBB+1与多种疾病有关。UBB+1不能作为泛素分子发挥作用，它本身是泛素/蛋白酶体系统（UPS）降解的底物。UBB+1的积累损害蛋白酶体系统并增强毒性蛋白质聚集，最终导致细胞死亡。在这里，我们描述了一种新的模型系统，以研究UBB+1如何损害UPS功能，以及它是否在蛋白质聚集中起着因果作用。我们在酵母中表达了类似于UBB+1的蛋白质（Ubext），并证明它会导致UPS受损。阻断Ubext的泛素化或减弱其与其他泛素加工蛋白的相互作用可降低UPS损伤。Ubext的表达改变了野生型泛素与UPS底物的结合。Ubext的表达显著增强了细胞对有毒蛋白聚集体的易感性，但令人惊讶的是，在酵母中并没有诱导或改变无毒蛋白聚集体。总之，这些结果表明，Ubext与一种以上的蛋白质相互作用，引起UPS的损害和影响蛋白质聚集体毒性。此外，我们提出了一个模型，慢性UPS损伤可能会造成有害的后果，对适当的蛋白质聚集体螯合。细胞毒性蛋白聚集体的积累发生在许多神经退行性疾病中。很难确定在这些疾病中发现的蛋白质聚集体是否代表疾病的原因或后果。降解途径，如泛素/蛋白酶体系统（UPS），去除容易聚集的错误折叠蛋白质。UPS涉及许多参与者，这些参与者协同工作以靶向蛋白质，以供蛋白酶体降解。泛素的突变形式与许多疾病有关，包括阿尔茨海默病。我们开发了一个酵母模型的突变体泛素蛋白，以研究其对UPS功能和蛋白质聚集的影响。我们证明，这种突变的泛素导致UPS的损害，并建议它这样做，通过与多个组件的途径相互作用。使用该模型，我们评估了突变体泛素对无毒蛋白质聚集体的影响，发现它们不会因其存在而改变。我们证明，突变体泛素作为一种修饰剂，通过改变UPS功能和底物泛素化，增加细胞对有害蛋白聚集体表型效应的易感性。此外，我们开发的系统可用于进一步了解蛋白酶体损伤和蛋白质聚集体毒性的复杂相互作用。
Protein homeostasis is critical for cellular survival and its dysregulation has been implicated in Alzheimer's disease (AD) and other neurodegenerative disorders. Despite the growing appreciation of the pathogenic mechanisms involved in familial forms of AD, much less is known about the sporadic cases. Aggregates found in both familial and sporadic AD often include proteins other than those typically associated with the disease. One such protein is a mutant form of ubiquitin, UBB+1, a frameshift product generated by molecular misreading of a wild-type ubiquitin gene. UBB+1 has been associated with multiple disorders. UBB+1 cannot function as a ubiquitin molecule, and it is itself a substrate for degradation by the ubiquitin/proteasome system (UPS). Accumulation of UBB+1 impairs the proteasome system and enhances toxic protein aggregation, ultimately resulting in cell death. Here, we describe a novel model system to investigate how UBB+1 impairs UPS function and whether it plays a causal role in protein aggregation. We expressed a protein analogous to UBB+1 in yeast (Ubext) and demonstrated that it caused UPS impairment. Blocking ubiquitination of Ubext or weakening its interactions with other ubiquitin-processing proteins reduced the UPS impairment. Expression of Ubext altered the conjugation of wild-type ubiquitin to a UPS substrate. The expression of Ubext markedly enhanced cellular susceptibility to toxic protein aggregates but, surprisingly, did not induce or alter nontoxic protein aggregates in yeast. Taken together, these results suggest that Ubext interacts with more than one protein to elicit impairment of the UPS and affect protein aggregate toxicity. Furthermore, we suggest a model whereby chronic UPS impairment could inflict deleterious consequences on proper protein aggregate sequestration. The accumulation of cytotoxic protein aggregates occurs in many neurodegenerative diseases. It is difficult to determine if the protein aggregates found in these diseases represent a cause or consequence of the disorder. Degradation pathways, such as the ubiquitin/proteasome system (UPS), remove misfolded proteins that are prone to aggregate. The UPS involves many players that work in concert to target proteins for degradation by the proteasome. A mutant form of ubiquitin has been associated with many diseases, including Alzheimer's disease. We developed a yeast model of the mutant ubiquitin protein in order to investigate its effect on UPS function and protein aggregation. We demonstrate that this mutant ubiquitin causes impairment of the UPS and suggest that it does so by interacting with multiple components of the pathway. Using this model, we evaluated the effects of the mutant ubiquitin on nontoxic protein aggregates and found that they were unaltered by its presence. We demonstrate that the mutant ubiquitin acts as a modifier, which increases cellular susceptibility to the phenotypic effects of deleterious protein aggregates by altering UPS functionality and substrate ubiquitination. Furthermore, the system we developed can be utilized to further understand the complex interplay of proteasomal impairment and protein aggregate toxicity.
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影响因子：
2.6
作者：
CHERNOFF, YO;INGEVECHTOMOV, SG;TERAVANESYAN, MD
通讯作者：
TERAVANESYAN, MD
影响因子：
4.8
作者：
Allen, Kim D.;Chernova, Tatiana A.;Chernoff, Yury O.
通讯作者：
Chernoff, Yury O.
影响因子：
64.5
作者：
FINLEY, D;OZKAYNAK, E;VARSHAVSKY, A
通讯作者：
VARSHAVSKY, A
影响因子：
56.9
作者：
GHODA, L;WETTERS, TV;COFFINO, P
通讯作者：
COFFINO, P
影响因子：
4.8
作者：
Chernova, TA;Allen, KD;Wilkinson, KD
通讯作者：
Wilkinson, KD