Metazoan Hsp70 machines use Hsp110 to power protein disaggregation
Metazoan Hsp70 machines use Hsp110 to power protein disaggregation
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DOI：
10.1038/emboj.2012.264
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发表时间：
2012-11-05
期刊：
影响因子：
11.4
通讯作者：
Bukau, Bernd
中科院分区：
文献类型：
--
作者：
Rampelt, Heike;Kirstein-Miles, Janine;Bukau, Bernd
易于聚集的错误折叠蛋白质的积累会破坏正常的细胞功能并促进衰老和疾病。细菌、真菌和植物通过强大的胞质 ATP 依赖性双分子伴侣系统（包括 AAA+ 解聚酶 Hsp100 和 Hsp70-Hsp40 系统）溶解和重折叠聚集蛋白，从而抵消这种情况。然而，后生动物缺乏 Hsp100 分解酶。我们发现，Hsp70 超家族的 Hsp110 成员重塑了人类 Hsp70-Hsp40 系统，能够在体外和细胞提取物中有效地解聚和重新折叠热和化学变性蛋白质的聚集体。这种 Hsp110 效应依赖于核苷酸交换，而不是 ATP 酶活性，这意味着不需要 ATP 驱动的陪伴。线虫秀丽隐杆线虫 Hsp110 的敲低，而不是无关的核苷酸交换因子，会损害热诱导的蛋白质聚集体的溶解，并严重缩短热休克后的寿命。我们得出的结论是，在后生动物中，由 Hsp110 核苷酸交换驱动的 Hsp70-Hsp40 代表了重建蛋白质稳态以抵消蛋白质解折叠应激的关键解聚机制。 EMBO 杂志 (2012) 31, 4221-4235。 doi：10.1038/emboj.2012.264； 2012 年 9 月 18 日在线发布
Accumulation of aggregation-prone misfolded proteins disrupts normal cellular function and promotes ageing and disease. Bacteria, fungi and plants counteract this by solubilizing and refolding aggregated proteins via a powerful cytosolic ATP-dependent bichaperone system, comprising the AAA+ disaggregase Hsp100 and the Hsp70-Hsp40 system. Metazoa, however, lack Hsp100 disaggregases. We show that instead the Hsp110 member of the Hsp70 superfamily remodels the human Hsp70-Hsp40 system to efficiently disaggregate and refold aggregates of heat and chemically denatured proteins in vitro and in cell extracts. This Hsp110 effect relies on nucleotide exchange, not on ATPase activity, implying ATP-driven chaperoning is not required. Knock-down of nematode Caenorhabditis elegans Hsp110, but not an unrelated nucleotide exchange factor, compromises dissolution of heat-induced protein aggregates and severely shortens lifespan after heat shock. We conclude that in metazoa, Hsp70-Hsp40 powered by Hsp110 nucleotide exchange represents the crucial disaggregation machinery that reestablishes protein homeostasis to counteract protein unfolding stress. The EMBO Journal (2012) 31, 4221-4235. doi: 10.1038/emboj.2012.264; Published online 18 September 2012