Absence of the Yeast Hsp31 Chaperones of the DJ-1 Superfamily Perturbs Cytoplasmic Protein Quality Control in Late Growth Phase
Absence of the Yeast Hsp31 Chaperones of the DJ-1 Superfamily Perturbs Cytoplasmic Protein Quality Control in Late Growth Phase
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DOI：
10.1371/journal.pone.0140363
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发表时间：
2015-10-14
期刊：
影响因子：
3.7
通讯作者：
Wolf, Dieter H.
中科院分区：
文献类型：
--
作者：
Amm, Ingo;Norell, Derrick;Wolf, Dieter H.
酿酒酵母热休克蛋白 Hsp31、Hsp32、Hsp33 和 Hsp34 属于 DJ-1/ThiJ/PfpI 超家族，其中最重要的成员包括人类蛋白 DJ-1 (PARK7)。 DJ-1 基因突变与常染色体隐性遗传、早发性帕金森病直接相关。 DJ-1 充当氧化应激诱导的伴侣，防止 α-突触核蛋白聚集和纤维化，而α-突触核蛋白是疾病发展的关键因素。使用模型底物 Delta ssCPY*Leu2myc (Delta ssCL*myc) 作为易于聚集的错误折叠细胞质蛋白，在酿酒酵母中进行体内测定，揭示了 Hsp31 分子伴侣家族对该底物稳态水平的影响。与 N 端规则途径 Ubr1 的泛素连接酶（已知其主要参与错误折叠胞质蛋白的降解过程）相比，Hsp31 伴侣家族的缺失不会损害新合成的错误折叠底物的降解。此外，对 Ubr1 具有强亲和力的底物（如含有 1 型 N-降解决定子精氨酸的底物）的降解也不受 Hsp31 伴侣家族缺失的影响。上位性分析表明，Hsp31 伴侣家族的一个功能存在于与错误折叠的细胞质蛋白的 Ubr1 依赖性降解重叠的途径中。该途径在营养限制条件下的生长后期具有相关性。此外，Hsp31 伴侣似乎对于维持细胞 Ssa Hsp70 活性很重要，这对于 Ubr1 依赖性降解很重要。
The Saccharomyces cerevisiae heat shock proteins Hsp31, Hsp32, Hsp33 and Hsp34 belong to the DJ-1/ThiJ/PfpI superfamily which includes the human protein DJ-1 (PARK7) as the most prominent member. Mutations in the DJ-1 gene are directly linked to autosomal recessive, early-onset Parkinson's disease. DJ-1 acts as an oxidative stress-induced chaperone preventing aggregation and fibrillation of a-synuclein, a critical factor in the development of the disease. In vivo assays in Saccharomyces cerevisiae using the model substrate Delta ssCPY*Leu2myc (Delta ssCL*myc) as an aggregation-prone misfolded cytoplasmic protein revealed an influence of the Hsp31 chaperone family on the steady state level of this substrate. In contrast to the ubiquitin ligase of the N-end rule pathway Ubr1, which is known to be prominently involved in the degradation process of misfolded cytoplasmic proteins, the absence of the Hsp31 chaperone family does not impair the degradation of newly synthesized misfolded substrate. Also degradation of substrates with strong affinity to Ubr1 like those containing the type 1 N-degron arginine is not affected by the absence of the Hsp31 chaperone family. Epistasis analysis indicates that one function of the Hsp31 chaperone family resides in a pathway overlapping with the Ubr1-dependent degradation of misfolded cytoplasmic proteins. This pathway gains relevance in late growth phase under conditions of nutrient limitation. Additionally, the Hsp31 chaperones seem to be important for maintaining the cellular Ssa Hsp70 activity which is important for Ubr1-dependent degradation.