Imbalance of Hsp70 family variants fosters tau accumulation
Imbalance of Hsp70 family variants fosters tau accumulation
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DOI：
10.1096/fj.12-220889
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发表时间：
2013-04-01
期刊：
影响因子：
4.8
通讯作者：
Dickey, Chad A.
中科院分区：
文献类型：
--
作者：
Jinwal, Umesh K.;Akoury, Elias;Dickey, Chad A.
功能失调的tau蛋白积累是tau病的一个主要因素，热休克蛋白70 （Hsp70）似乎在这种积累中起重要作用。一些报道表明，Hsp70蛋白可以导致tau蛋白的降解加速或减慢，但这些相反的活性是如何被控制的尚不清楚。在这里，我们证明了Hsp70家族的高度同源变异可以对tau清除动力学产生相反的影响。当在四环素（Tet）蛋白追逐模型中过表达时，组成型热休克同源蛋白70 （Hsc70）和诱导型Hsp72分别减缓或加速tau蛋白的清除。在含有罗丹明标记的微管蛋白和人重组Hsp72和Hsc70的重组爪蟾提取物中，Tau蛋白与Hsc70而非Hsp72协同作用，促进微管组装的速度几乎是Hsp70同源物的两倍。人重组蛋白核磁共振谱分析结果显示，Hsp72对tau蛋白的亲和力高于Hsc70 (I/I-0比值差0.3)，但Hsc70在人和小鼠脑组织中的丰富度是Hsp72的30倍。这表明大脑中主要的Hsp70变体是Hsc70，这表明大脑环境主要支持较慢的tau清除。尽管Hsp72具有清除tau蛋白的能力，但它在阿尔茨海默病的大脑中并没有被诱导，这表明该疾病的发病机制与年龄有关。通过使用混合Hsp72和Hsc70结构域的嵌合体，我们确定Hsc70和Hsp72在tau清除动力学方面存在这些差异的原因在于它们的c端结构域，这对于它们与底物和辅伴侣的相互作用至关重要。Hsp72而不是Hsc70在tau存在时能够募集协伴侣泛素连接酶CHIP，这是已知的促进tau泛素化的酶，描述了这些同源Hsp70变体的c端如何差异调节tau分类的可能机制。因此，促进Hsp72表达和抑制Hsc70的努力可能与牛头病变的治疗相关。-Jinwal, uk, Akoury， E, Abisambra， J. F， O'Leary， J. C.， III, Thompson， A. D, Blair， L. J., Jin， Y., Bacon， J., Nordhues， B. A., Cockman， M., Zhang， J., Li， P., Zhang， B., Borysov， S., Uversky， V. N., Biernat， J., Mandelkow， E., Gestwicki， J., Zweckstetter， M., Dickey， C.。中国生物医学工程学报，2013,32(2):559 - 559。www.fasebj.org
Dysfunctional tau accumulation is a major contributing factor in tauopathies, and the heat-shock protein 70 (Hsp70) seems to play an important role in this accumulation. Several reports suggest that Hsp70 proteins can cause tau degradation to be accelerated or slowed, but how these opposing activities are controlled is unclear. Here we demonstrate that highly homologous variants in the Hsp70 family can have opposing effects on tau clearance kinetics. When overexpressed in a tetracycline (Tet)-based protein chase model, constitutive heat shock cognate 70 (Hsc70) and inducible Hsp72 slowed or accelerated tau clearance, respectively. Tau synergized with Hsc70, but not Hsp72, to promote microtubule assembly at nearly twice the rate of either Hsp70 homologue in reconstituted, ATP-regenerating Xenopus extracts supplemented with rhodamine-labeled tubulin and human recombinant Hsp72 and Hsc70. Nuclear magnetic resonance spectroscopy with human recombinant protein revealed that Hsp72 had greater affinity for tau than Hsc70 (I/I-0 ratio difference of 0.3), but Hsc70 was 30 times more abundant than Hsp72 in human and mouse brain tissue. This indicates that the predominant Hsp70 variant in the brain is Hsc70, suggesting that the brain environment primarily supports slower tau clearance. Despite its capacity to clear tau, Hsp72 was not induced in the Alzheimer's disease brain, suggesting a mechanism for age-associated onset of the disease. Through the use of chimeras that blended the domains of Hsp72 and Hsc70, we determined that the reason for these differences between Hsc70 and Hsp72 with regard to tau clearance kinetics lies within their C-terminal domains, which are essential for their interactions with substrates and cochaperones. Hsp72 but not Hsc70 in the presence of tau was able to recruit the cochaperone ubiquitin ligase CHIP, which is known to facilitate the ubiquitination of tau, describing a possible mechanism of how the C-termini of these homologous Hsp70 variants can differentially regulate tau triage. Thus, efforts to promote Hsp72 expression and inhibit Hsc70 could be therapeutically relevant for tauopathies.-Jinwal, U. K., Akoury, E., Abisambra, J. F., O'Leary, J. C., III, Thompson, A. D., Blair, L. J., Jin, Y., Bacon, J., Nordhues, B. A., Cockman, M., Zhang, J., Li, P., Zhang, B., Borysov, S., Uversky, V. N., Biernat, J., Mandelkow, E., Gestwicki, J. E., Zweckstetter, M., Dickey, C. A. Imbalance of Hsp70 family variants fosters tau accumulation. FASEB J. 27, 1450-1459 (2013). www.fasebj.org