The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress
The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress
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DOI：
10.1016/s0092-8674(03)00939-5
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发表时间：
2003-12-12
期刊：
影响因子：
64.5
通讯作者：
Yao, TP
中科院分区：
文献类型：
--
作者：
Kawaguchi, Y;Kovacs, JJ;Yao, TP
有效清除细胞毒性错误折叠的蛋白质聚集体对细胞生存至关重要。错误折叠的蛋白质聚集体被动力蛋白马达通过微管网络从细胞质运输和移除到一个被称为侵袭体的新细胞器，在那里它们被加工。然而，动力蛋白马达识别错误折叠的蛋白质片段的方式，以及调节侵袭体形成的细胞因素仍不清楚。我们发现，HDAC6是一种微管相关的脱乙酰酶，是侵袭体的一个组成部分。我们证明了HDAC6具有结合多泛素化的错误折叠蛋白和动力蛋白马达的能力，从而将错误折叠的蛋白质货物招募到动力蛋白马达以运输到侵略体。事实上，缺乏HDAC6的细胞不能从细胞质中清除错误折叠的蛋白质聚集体，不能正确地形成侵袭体，并且对错误折叠蛋白质的积累高度敏感。这些发现表明，HDAC6在错误折叠的蛋白质诱导的应激的细胞管理中起着关键作用。
The efficient clearance of cytotoxic misfolded protein aggregates is critical for cell survival. Misfolded protein aggregates are transported and removed from the cytoplasm by dynein motors via the microtubule network to a novel organelle termed the aggresome where they are processed. However, the means by which dynein motors recognize misfolded protein cargo, and the cellular factors that regulate aggresome formation, remain unknown. We have discovered that HDAC6, a microtubule-associated deacetylase, is a component of the aggresome. We demonstrate that HDAC6 has the capacity to bind both polyubiquitinated misfolded proteins and dynein motors, thereby acting to recruit misfolded protein cargo to dynein motors for transport to aggresomes. Indeed, cells deficient in HDAC6 fail to clear misfolded protein aggregates from the cytoplasm, cannot form aggresomes properly, and are hypersensitive to the accumulation of misfolded proteins. These findings identify HDAC6 as a crucial player in the cellular management of misfolded protein-induced stress.