Chaperone AMPylation modulates aggregation and toxicity of neurodegenerative disease-associated polypeptides.
Chaperone AMPylation modulates aggregation and toxicity of neurodegenerative disease-associated polypeptides.
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DOI：
10.1073/pnas.1801989115
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发表时间：
2018-05-29
影响因子：
11.1
通讯作者：
Ploegh HL
中科院分区：
文献类型：
--
作者：
Truttmann MC;Pincus D;Ploegh HL
真核生物中蛋白质ampyation是一种相对较少研究的翻译后修饰。除了酵母外，所有真核生物都有执行这种修饰所需的酶机制。不同细胞区室中的热休克蛋白家族成员似乎是ampyation的首选靶标，但事实证明，引证其生物学功能具有挑战性。我们发现，通过产生零等位基因和AMPylase FIC-1的组成型活性版本，影响AMPylase状态的遗传修饰可以对秀丽隐杆线虫对与蛋白质聚集相关的神经退行性疾病的易感性产生重大影响。蛋白质静止是维持生物体活力的关键，这一过程被衰老依赖的蛋白质聚集所抵消。热休克蛋白（HSP）家族的伴侣蛋白通过减少未折叠蛋白的负担来帮助控制蛋白质稳态。它们还监督蛋白质聚集体的形成。在这里，我们探讨了ampyation，一种翻译后的蛋白质修饰，已经成为HSP70活性的强大调节剂，如何影响蛋白质聚集的动力学。我们发现秀丽隐杆线虫细胞ampyylation水平的调整直接影响淀粉样蛋白-β (a β)、聚谷氨酰胺延伸多肽（polyQ）和α-突触核蛋白（α-syn）的聚集特性和相关毒性。在自身启动子下表达具有组成活性的秀丽隐杆线虫AMPylase FIC-1(E274G)，可加速a β和α-syn的聚集，并显著降低其毒性。ampyation的缺乏降低了细胞对易于聚集的polyQ蛋白的耐受性，并改变了它们的聚集行为。FIC-1（E274G）的过表达会干扰细胞存活和幼虫发育，因此需要严格控制体内AMPylase的活性。因此，我们在神经退行性疾病模型中定义了HSP70 ampyation与蛋白质聚集动力学之间的联系。我们的结果与细胞保护一致，而不是细胞毒性，作用于这种蛋白质聚集体。
Protein AMPylation in eukaryotes is a comparatively understudied posttranslational modification. With the exception of yeast, all eukaryotes have the enzymatic machinery required to execute this modification. Members of the heat shock protein family in different cellular compartments appear to be preferred targets for AMPylation, but it has proven challenging to adduce its biological function. We show that genetic modifications that affect AMPylation status, through generation of null alleles and a constitutively active version of the AMPylase FIC-1, can have a major impact on the susceptibility of Caenorhabditis elegans to neurodegenerative conditions linked to protein aggregation. Proteostasis is critical to maintain organismal viability, a process counteracted by aging-dependent protein aggregation. Chaperones of the heat shock protein (HSP) family help control proteostasis by reducing the burden of unfolded proteins. They also oversee the formation of protein aggregates. Here, we explore how AMPylation, a posttranslational protein modification that has emerged as a powerful modulator of HSP70 activity, influences the dynamics of protein aggregation. We find that adjustments of cellular AMPylation levels in Caenorhabditis elegans directly affect aggregation properties and associated toxicity of amyloid-β (Aβ), of a polyglutamine (polyQ)-extended polypeptide, and of α-synuclein (α-syn). Expression of a constitutively active C. elegans AMPylase FIC-1(E274G) under its own promoter expedites aggregation of Aβ and α-syn, and drastically reduces their toxicity. A deficiency in AMPylation decreases the cellular tolerance for aggregation-prone polyQ proteins and alters their aggregation behavior. Overexpression of FIC-1(E274G) interferes with cell survival and larval development, underscoring the need for tight control of AMPylase activity in vivo. We thus define a link between HSP70 AMPylation and the dynamics of protein aggregation in neurodegenerative disease models. Our results are consistent with a cytoprotective, rather than a cytotoxic, role for such protein aggregates.
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