The absence of specific yeast heat-shock proteins leads to abnormal aggregation and compromised autophagic clearance of mutant Huntingtin proteins.
The absence of specific yeast heat-shock proteins leads to abnormal aggregation and compromised autophagic clearance of mutant Huntingtin proteins.
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缺乏特定的酵母热蛋白会导致异常聚集，并损害突变体亨廷汀蛋白的自噬清除率。
DOI：
10.1371/journal.pone.0191490
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Higgins R;Kabbaj MH;Hatcher A;Wang Y
蛋白质的功能取决于其正确的折叠，但新合成的蛋白质容易发生异常折叠和聚集。热休克蛋白（HSP）作为分子伴侣，有助于蛋白质折叠和降解错误折叠的蛋白质。亨廷顿基因（HTT）中的三核苷酸（CAG）重复扩增导致错误折叠的亨廷顿蛋白（Htt）的表达，这有助于亨廷顿病的发展。我们以前发现，突变的Htt与polyQ扩展（Htt 103 QP）的降解依赖于泛素蛋白酶体系统和自噬。然而，热休克蛋白在清除突变的Htt中的作用仍然知之甚少。在这里，我们报告说，胞质Hsp 70（Ssa家族），其核苷酸交换因子（Sse 1和Fes 1），和Hsp 40共伴侣（Ydj 1）所需的包涵体形成的Htt 103 QP蛋白和它们的清除通过自噬。延长诱导的Htt 103 QP-GFP导致在野生型酵母细胞中形成单个包涵体，但缺乏这些HSP的突变体细胞表现出增加的Htt 103 QP聚集体的数量。最值得注意的是，我们使用琼脂糖凝胶分析在sse 1 Δ突变细胞中检测到更多聚集形式的Htt 103 QP。即使在没有Htt 103 QP过表达的情况下，在这些HSP突变体中也观察到增加的蛋白质聚集体。重要的是，这些HSP是自噬介导的Htt 103 QP清除所需的，但对蛋白酶体依赖性降解不太重要。这些发现表明伴侣网络促进错误折叠蛋白质的包涵体形成和随后的自噬清除。
The functionality of a protein depends on its correct folding, but newly synthesized proteins are susceptible to aberrant folding and aggregation. Heat shock proteins (HSPs) function as molecular chaperones that aid in protein folding and the degradation of misfolded proteins. Trinucleotide (CAG) repeat expansion in the Huntingtin gene (HTT) results in the expression of misfolded Huntingtin protein (Htt), which contributes to the development of Huntington’s disease. We previously found that the degradation of mutated Htt with polyQ expansion (Htt103QP) depends on both ubiquitin proteasome system and autophagy. However, the role of heat shock proteins in the clearance of mutated Htt remains poorly understood. Here, we report that cytosolic Hsp70 (Ssa family), its nucleotide exchange factors (Sse1 and Fes1), and a Hsp40 co-chaperone (Ydj1) are required for inclusion body formation of Htt103QP proteins and their clearance via autophagy. Extended induction of Htt103QP-GFP leads to the formation of a single inclusion body in wild-type yeast cells, but mutant cells lacking these HSPs exhibit increased number of Htt103QP aggregates. Most notably, we detected more aggregated forms of Htt103QP in sse1Δ mutant cells using an agarose gel assay. Increased protein aggregates are also observed in these HSP mutants even in the absence Htt103QP overexpression. Importantly, these HSPs are required for autophagy-mediated Htt103QP clearance, but are less critical for proteasome-dependent degradation. These findings suggest a chaperone network that facilitates inclusion body formation of misfolded proteins and the subsequent autophagic clearance.
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影响因子：
5.3
作者：
Kaimal JM;Kandasamy G;Gasser F;Andréasson C
通讯作者：
Andréasson C
影响因子：
4.7
作者：
de Oliveira GA;Rangel LP;Costa DC;Silva JL
通讯作者：
Silva JL
影响因子：
8.8
作者：
Brehme M;Voisine C;Rolland T;Wachi S;Soper JH;Zhu Y;Orton K;Villella A;Garza D;Vidal M;Ge H;Morimoto RI
通讯作者：
Morimoto RI
DOI：
10.1073/pnas.1402215111
发表时间：
2014-04-15
影响因子：
11.1
作者：
Bhat, Kavita P.;Yan, Sen;Li, Xiao-Jiang
通讯作者：
Li, Xiao-Jiang
影响因子：
4.8
作者：
Abrams, Jennifer L.;Verghese, Jacob;Morano, Kevin A.
通讯作者：
Morano, Kevin A.