DnaJA1 antagonizes constitutive Hsp70-mediated stabilization of tau.
DnaJA1 antagonizes constitutive Hsp70-mediated stabilization of tau.
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DOI：
10.1016/j.jmb.2012.02.003
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发表时间：
2012-08-24
影响因子：
5.6
通讯作者：
Dickey, Chad A.
中科院分区：
文献类型：
--
作者：
Abisambra, Jose F.;Jinwal, Umesh K.;Suntharalingam, Amirthaa;Arulselvam, Karthik;Brady, Sarah;Cockman, Matthew;Jin, Ying;Zhang, Bo;Dickey, Chad A.
Tau聚集和淀粉样蛋白生成是称为Tau蛋白病的神经退行性疾病的常见标志。分子伴侣网络构成了细胞对诸如tau聚集的损伤的防御。然而，分子伴侣对tau蛋白的作用是二分的。tau蛋白微管结合活性的丧失促进了不适当的分子伴侣相互作用，从而促进了淀粉样蛋白生成的tau蛋白构象。相反，其他分子伴侣能够促进tau清除。在这里，我们证明了一个关键的贡献tau分类是热休克蛋白70蛋白的DnaJ结合结构域。特别是，组成型DnaJ，DnaJA 1的过表达介导tau清除，而敲低促进tau积累。这种清除并不特异于不同的致病性tau种类。DnaJA 1的活性减弱伴随Hsp 70的增加。由DnaJA 1促进的Tau减少依赖于已知在人类阿尔茨海默氏症大脑中被聚泛素化的赖氨酸的完整性。在体内，DnaJA 1和tau水平呈负相关。DnaJA 1的作用是部分特异性的：DnaJA 1降低了polyQ蛋白的水平，但对α-突触核蛋白水平没有显著影响。这些数据表明，DnaJA 1对所有tau种类进行分类，以用于泛素依赖的清除机制。此外，DnaJA 1和Hsp 70的水平似乎对tau相互作用：随着DnaJA 1水平的增加，tau水平降低，但如果同时诱导Hsp 70水平，则可以防止这种情况。因此，DnaJ库可能代表了tau发病机制的一组强大的遗传修饰剂。进一步的研究可以提供有关分类决策的新见解，这些决策促进或预防tau蛋白和其他与神经退行性疾病相关的蛋白质的淀粉样变性。
Tau aggregation and amyloidogenesis are common hallmarks for neurodegenerative disorders called tauopathies. The molecular chaperone network constitutes the cellular defense against insults such as tau aggregation. However, chaperone effects on tau are dichotomous. Loss of tau’s microtubule-binding activity facilitates an inappropriate chaperone interaction that promotes an amyloidogenic tau conformation. Conversely, other chaperones are capable of promoting tau clearance. Here, we demonstrate that a critical contributor to tau triage is the DnaJ-binding domain of Hsp70 proteins. In particular, over-expression of the constitutive DnaJ, DnaJA1, mediated tau clearance, while knockdown facilitated tau accumulation. This clearance was not specific to distinct pathogenic tau species. The activity of DnaJA1 was attenuated by concomitant increases in Hsp70. Tau reductions facilitated by DnaJA1 were dependent on the integrity of lysines known to be poly-ubiquitinated in human Alzheimer’s brain. In vivo, DnaJA1 and tau levels were inversely correlated. The effects of DnaJA1 were partially specific: DnaJA1 reduced the levels of a polyQ protein but had no significant effect on α-synuclein levels. These data suggest that DnaJA1 triages all tau species for ubiquitin-dependent clearance mechanisms. Moreover, the levels of DnaJA1 and Hsp70 seem to play against each other with regard to tau: as DnaJA1 levels increase, tau levels are reduced, but this can be prevented if Hsp70 levels are simultaneously induced. Thus, the DnaJ repertoire possibly represents a powerful set of genetic modifiers for tau pathogenesis. Further investigations, could provide new insights about triage decisions that facilitate or prevent amyloidogenesis of tau and other proteins associated with neurodegenerative disease.
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影响因子：
4.2
作者：
Sarkar, Mitul;Kuret, Jeff;Lee, Gloria
通讯作者：
Lee, Gloria
DOI：
10.1083/jcb.139.5.1089
发表时间：
1997-12-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Terada K;Kanazawa M;Bukau B;Mori M
通讯作者：
Mori M
影响因子：
3.4
作者：
Brocchieri L;Conway de Macario E;Macario AJ
通讯作者：
Macario AJ
DOI：
10.1073/pnas.91.24.11343
发表时间：
1994-11-22
影响因子：
11.1
作者：
SZYPERSKI, T;PELLECCHIA, M;WUTHRICH, K
通讯作者：
WUTHRICH, K
影响因子：
56.9
作者：
SantaCruz, K;Lewis, J;Ashe, KH
通讯作者：
Ashe, KH