Hsc70 contributes to cancer cell survival by preventing Rab1A degradation under stress conditions.
Hsc70 contributes to cancer cell survival by preventing Rab1A degradation under stress conditions.
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DOI：
10.1371/journal.pone.0096785
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Iwao H
中科院分区：
文献类型：
--
作者：
Tanaka M;Mun S;Harada A;Ohkawa Y;Inagaki A;Sano S;Takahashi K;Izumi Y;Osada-Oka M;Wanibuchi H;Yamagata M;Yukimura T;Miura K;Shiota M;Iwao H
热休克同源蛋白70（Hsc 70）作为分子伴侣维持细胞内蛋白质，其允许癌细胞在蛋白毒性应激下存活。我们试图使用Hsc 70来识别癌细胞存活的关键分子。在这里，我们进行了基于质谱的蛋白质组学分析，利用亲和纯化与抗Hsc 70抗体，其结果是，83差异表达的蛋白质被确定在应力条件下。这一结果表明，有一个变化的蛋白质与Hsc 70相互作用，以响应压力。在血清耗竭和5-氟尿嘧啶处理条件下鉴定的蛋白质中，Rab 1A被鉴定为癌细胞存活的必需分子。Hsc 70与Rab 1A以分子伴侣依赖的方式相互作用。此外，Hsc 70敲除降低了Rab 1A的水平，并增加了其在应激条件下的遍在蛋白化水平，这表明Hsc 70阻止了应激暴露变性的Rab 1A的降解。我们还发现Rab 1A敲低通过抑制自噬体形成诱导细胞死亡。因此，Rab 1A可能有助于克服蛋白毒性损伤，使癌细胞在应激条件下存活。Hsc 70相互作用物的分析提供了对细胞内状态变化的洞察。我们期望对Hsc 70相互作用组的进一步研究能够提供对癌细胞生理学更全面的理解。
Heat shock cognate protein 70 (Hsc70) acts as a molecular chaperone for the maintenance of intracellular proteins, which allows cancer cells to survive under proteotoxic stress. We attempted to use Hsc70 to identify key molecules in cancer cell survival. Here, we performed mass-spectrometry-based proteomics analysis utilizing affinity purification with anti-Hsc70 antibodies; as a result, 83 differentially expressed proteins were identified under stress conditions. This result implies that there was a change in the proteins with which Hsc70 interacted in response to stress. Among the proteins identified under both serum-depleted and 5-fluorouracil-treated conditions, Rab1A was identified as an essential molecule for cancer cell survival. Hsc70 interacted with Rab1A in a chaperone-dependent manner. In addition, Hsc70 knockdown decreased the level of Rab1A and increased the level of its ubiquitination under stress conditions, suggesting that Hsc70 prevented the degradation of Rab1A denatured by stress exposure. We also found that Rab1A knockdown induced cell death by inhibition of autophagosome formation. Rab1A may therefore contribute to overcoming proteotoxic insults, which allows cancer cells to survive under stress conditions. Analysis of Hsc70 interactors provided insight into changes of intracellular status. We expect further study of the Hsc70 interactome to provide a more comprehensive understanding of cancer cell physiology.
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