Dual roles of HSP70 chaperone HSPA1 in quality control of nascent and newly synthesized proteins.
Dual roles of HSP70 chaperone HSPA1 in quality control of nascent and newly synthesized proteins.
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HSP70 伴侣 HSPA1 在新生和新合成蛋白质质量控制中的双重作用
DOI：
10.15252/embj.2020106183
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发表时间：
2021-07-01
期刊：
影响因子：
--
通讯作者：
Wolf DA
中科院分区：
文献类型：
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作者：
Tian G;Hu C;Yun Y;Yang W;Dubiel W;Cheng Y;Wolf DA
暴露在热应激下会触发一种明确的急性反应，其特征是HSF1依赖的热休克蛋白转录上调。被允许恢复的细胞获得了耐热性，但人们对这种适应知之甚少。通过定量蛋白质组学，我们发现在获得耐热的MCF7乳腺癌细胞中，HSP70家族伴侣HSPA1及其辅助因子HSPH1和DNAJB1选择性上调。HSPA1被发现在热应激反应中具有双重功能：(I)在急性应激期间，它促进26S蛋白酶体招募到翻译核糖体，从而平衡细胞快速蛋白质降解和恢复蛋白质合成；(Ii)在热耐受期间，HSPA1与HSPH1一起维持泛素化的新生/新合成的蛋白质处于可溶状态，这是有效清除蛋白酶体所需的。一直以来，HSPH1的缺失阻碍了小鼠的耐热性和食道癌的生长，从而为HSPH1高表达的消化道癌症预后不良提供了潜在的解释，并提名HSPH1作为抗癌药物的靶点。我们提出HSPA1单独或与HSPH1和DNAJB1复合在促进新生/新合成蛋白质的质量控制和细胞耐热性方面的双重作用。获得耐热性的细胞的定量蛋白质组学显示，热休克蛋白上调，促进蛋白酶体清除新生多肽，并迅速恢复蛋白质合成。
Exposure to heat stress triggers a well‐defined acute response marked by HSF1‐dependent transcriptional upregulation of heat shock proteins. Cells allowed to recover acquire thermotolerance, but this adaptation is poorly understood. By quantitative proteomics, we discovered selective upregulation of HSP70‐family chaperone HSPA1 and its co‐factors, HSPH1 and DNAJB1, in MCF7 breast cancer cells acquiring thermotolerance. HSPA1 was found to have dual function during heat stress response: (i) During acute stress, it promotes the recruitment of the 26S proteasome to translating ribosomes, thus poising cells for rapid protein degradation and resumption of protein synthesis upon recovery; (ii) during thermotolerance, HSPA1 together with HSPH1 maintains ubiquitylated nascent/newly synthesized proteins in a soluble state required for their efficient proteasomal clearance. Consistently, deletion of HSPH1 impedes thermotolerance and esophageal tumor growth in mice, thus providing a potential explanation for the poor prognosis of digestive tract cancers with high HSPH1 and nominating HSPH1 as a cancer drug target. We propose dual roles of HSPA1 either alone or in complex with HSPH1 and DNAJB1 in promoting quality control of nascent/newly synthesized proteins and cellular thermotolerance. Quantitative proteomics in cells acquiring thermotolerance reveals upregulation of heat‐shock proteins that promote proteasomal clearance of nascent polypeptides and rapid resumption of protein synthesis.