Differential role of cytosolic Hsp70s in longevity assurance and protein quality control.
Differential role of cytosolic Hsp70s in longevity assurance and protein quality control.
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细胞质 Hsp70s 在长寿保证和蛋白质质量控制中的不同作用
DOI：
10.1371/journal.pgen.1008951
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发表时间：
2021-01
期刊：
影响因子：
4.5
通讯作者：
Nyström T
中科院分区：
文献类型：
--
作者：
Andersson R;Eisele-Bürger AM;Hanzén S;Vielfort K;Öling D;Eisele F;Johansson G;Gustafsson T;Kvint K;Nyström T
70 kDa热休克蛋白（Hsp 70）是蛋白质质量控制网络的重要分子伴侣，对细胞健康和寿命至关重要。酵母中的四种胞质Hsp 70，Ssa 1 -4，被认为是功能冗余的，但Ssa 1和Ssa 2的缺失导致细胞繁殖严重减少并加速复制老化。在我们的努力，以确定哪些热休克蛋白70的活动是最重要的长寿保证，我们系统地调查的能力，Ssa 4进行不同的活动进行的Ssa 1/2过度生产Ssa 4细胞缺乏这些Hsp 70分子伴侣。我们发现，Ssa 4，当在缺乏Ssa 1/2的细胞中过度产生时，拯救生长，减轻聚集体形成，恢复聚集体到蛋白质内含物中的空间沉积，并促进蛋白质降解。相比之下，Ssa 4在Hsp 70缺陷细胞中的过量生产未能恢复解聚酶Hsp 104对错误折叠/聚集蛋白的募集，完全恢复蛋白聚集体的清除，并带回核仁相关聚集区室的形成。将Ssa 4的核苷酸结合结构域与Ssa 1的核苷酸结合结构域交换抑制了Ssa 4的这种“缺陷”。有趣的是，Ssa 4的过量生产延长了ssa 1 Δ ssa 2 Δ突变细胞的短寿命，使其寿命与野生型细胞相当，甚至更长，这表明热休克蛋白104依赖性聚集体清除不是酵母寿命保证的先决条件。所有生物体都有蛋白质，这些蛋白质相互连接在一起，在整个生命周期中稳定和保护细胞。其中一种蛋白质是热休克蛋白70（Hsp 70）。Hsp 70蛋白参与将其他蛋白质折叠成其功能形式，将蛋白质从聚集体中解开，组织细胞内的聚集体并确保破坏受损蛋白质。在这项研究中，我们研究了酵母中三种密切相关的Hsp 70蛋白; Ssa 1，2和4，试图描述Ssa 4与Ssa 1和2相比的功能差异，并回答这个问题：什么类型的细胞应激保护是达到正常寿命所必需的？我们表明，Ssa 4可以执行许多相同的任务，Ssa 1和2，但Ssa 4不相互作用的方式与Ssa 1和2与其他类型的蛋白质。这导致热应激后产生的蛋白质聚集体的去除延迟。ssa 4也不能确保错误折叠的蛋白质在细胞核内正确聚集。然而，事实证明，这并不是酵母细胞实现完整寿命所必需的，这向我们表明，只要细胞能够首先防止聚集体形成，它们就可以达到完整的寿命。
70 kDa heat shock proteins (Hsp70) are essential chaperones of the protein quality control network; vital for cellular fitness and longevity. The four cytosolic Hsp70’s in yeast, Ssa1-4, are thought to be functionally redundant but the absence of Ssa1 and Ssa2 causes a severe reduction in cellular reproduction and accelerates replicative aging. In our efforts to identify which Hsp70 activities are most important for longevity assurance, we systematically investigated the capacity of Ssa4 to carry out the different activities performed by Ssa1/2 by overproducing Ssa4 in cells lacking these Hsp70 chaperones. We found that Ssa4, when overproduced in cells lacking Ssa1/2, rescued growth, mitigated aggregate formation, restored spatial deposition of aggregates into protein inclusions, and promoted protein degradation. In contrast, Ssa4 overproduction in the Hsp70 deficient cells failed to restore the recruitment of the disaggregase Hsp104 to misfolded/aggregated proteins, to fully restore clearance of protein aggregates, and to bring back the formation of the nucleolus-associated aggregation compartment. Exchanging the nucleotide-binding domain of Ssa4 with that of Ssa1 suppressed this ‘defect’ of Ssa4. Interestingly, Ssa4 overproduction extended the short lifespan of ssa1Δ ssa2Δ mutant cells to a lifespan comparable to, or even longer than, wild type cells, demonstrating that Hsp104-dependent aggregate clearance is not a prerequisite for longevity assurance in yeast. All organisms have proteins that network together to stabilize and protect the cell throughout its lifetime. One of these types of proteins are the Hsp70s (heat shock protein 70). Hsp70 proteins take part in folding other proteins to their functional form, untangling proteins from aggregates, organize aggregates inside the cell and ensure that damaged proteins are destroyed. In this study, we investigated three closely related Hsp70 proteins in yeast; Ssa1, 2 and 4, in an effort to describe the functional difference of Ssa4 compared to Ssa1 and 2 and to answer the question: What types of cellular stress protection are necessary to reach a normal lifespan? We show that Ssa4 can perform many of the same tasks as Ssa1 and 2, but Ssa4 doesn’t interact in the same manner as Ssa1 and 2 with other types of proteins. This leads to a delay in removing protein aggregates created after heat stress. Ssa4 also cannot ensure that misfolded proteins aggregate correctly inside the nucleus of the cell. However, this turns out not to be necessary for yeast cells to achieve a full lifespan, which shows us that as long as cells can prevent aggregates from forming in the first place, they can reach a full lifespan.
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DOI：
10.1023/b:visi.0000029664.99615.94
发表时间：
2004-11-01
影响因子：
19.5
作者：
Lowe, DG
通讯作者：
Lowe, DG
表达SSA1，SSA2，SSA3或SSA4的酵母细胞的全局转录本和表型分析是胞质HSP70-SSA伴侣活性的唯一来源。
影响因子：
4.4
作者：
Hasin N;Cusack SA;Ali SS;Fitzpatrick DA;Jones GW
通讯作者：
Jones GW
影响因子：
64.5
作者：
Hanzen, Sarah;Vielfort, Katarina;Nystrom, Thomas
通讯作者：
Nystrom, Thomas
影响因子：
8
作者：
Mayer, MP;Bukau, B
通讯作者：
Bukau, B
DOI：
10.1073/pnas.1217988110
发表时间：
2013-05-21
影响因子：
11.1
作者：
Lee, Jungsoon;Kim, Ji-Hyun;Tsai, Francis T. F.
通讯作者：
Tsai, Francis T. F.