PolyQ-expanded proteins impair cellular proteostasis of ataxin-3 through sequestering the co-chaperone HSJ1 into aggregates.
PolyQ-expanded proteins impair cellular proteostasis of ataxin-3 through sequestering the co-chaperone HSJ1 into aggregates.
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PolyQ 扩展蛋白通过将共伴侣 HSJ1 隔离成聚集体来损害 ataxin-3 的细胞蛋白质稳态
DOI：
10.1038/s41598-021-87382-w
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发表时间：
2021-04-09
影响因子：
4.6
通讯作者：
Hu HY
中科院分区：
文献类型：
--
作者：
Yue HW;Hong JY;Zhang SX;Jiang LL;Hu HY
蛋白质的多聚谷氨酰胺(PolyQ)膨胀可引发蛋白质错误折叠和淀粉样凝集，从而导致严重的细胞毒性，甚至相应的神经退行性疾病。然而，为什么多Q聚集对细胞有毒性还没有完全阐明。在这里，我们以多聚Q-展开(PQE)的ataxin-7(Atx7)和Huntingtin(Htt)片段为模型，研究多聚Q聚集体对内源性ataxin-3(Atx3)细胞蛋白稳定性的影响。Atx3是一种经常出现在各种包涵体中的蛋白质。我们发现，PQE、Atx7和Htt通过降低Atx3的可溶性水平和总Atx3水平，但促进聚集的形成，从而损害Atx3的细胞蛋白稳定性。这些多聚Q蛋白的表达促进了内源性Atx3蛋白酶体的降解及其聚集形式的积累。然后我们验证了辅助伴侣HSJ1是协调Atx3细胞蛋白稳定平衡的关键因子；并进一步发现PolyQ蛋白可以UIM结构域依赖的方式将HSJ1隔离成聚集体或包涵体。因此，Atx3蛋白稳态的受损可能与细胞内HSJ1的滞留和功能丧失有关。这项研究破译了PQE蛋白如何触发蛋白质病的潜在机制，并为支持劫持假说提供了额外的证据，该假说认为蛋白质聚集体隔离细胞相互作用伙伴会导致细胞毒性或神经退化。
Polyglutamine (polyQ) expansion of proteins can trigger protein misfolding and amyloid-like aggregation, which thus lead to severe cytotoxicities and even the respective neurodegenerative diseases. However, why polyQ aggregation is toxic to cells is not fully elucidated. Here, we took the fragments of polyQ-expanded (PQE) ataxin-7 (Atx7) and huntingtin (Htt) as models to investigate the effect of polyQ aggregates on the cellular proteostasis of endogenous ataxin-3 (Atx3), a protein that frequently appears in diverse inclusion bodies. We found that PQE Atx7 and Htt impair the cellular proteostasis of Atx3 by reducing its soluble as well as total Atx3 level but enhancing formation of the aggregates. Expression of these polyQ proteins promotes proteasomal degradation of endogenous Atx3 and accumulation of its aggregated form. Then we verified that the co-chaperone HSJ1 is an essential factor that orchestrates the balance of cellular proteostasis of Atx3; and further discovered that the polyQ proteins can sequester HSJ1 into aggregates or inclusions in a UIM domain-dependent manner. Thereby, the impairment of Atx3 proteostasis may be attributed to the sequestration and functional loss of cellular HSJ1. This study deciphers a potential mechanism underlying how PQE protein triggers proteinopathies, and also provides additional evidence in supporting the hijacking hypothesis that sequestration of cellular interacting partners by protein aggregates leads to cytotoxicity or neurodegeneration.
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DOI：
10.1523/jneurosci.2071-10.2010
发表时间：
2010-11-10
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Graham RK;Deng Y;Carroll J;Vaid K;Cowan C;Pouladi MA;Metzler M;Bissada N;Wang L;Faull RL;Gray M;Yang XW;Raymond LA;Hayden MR
通讯作者：
Hayden MR
影响因子：
64.5
作者：
Graham, Rona K.;Deng, Yu;Hayden, Michael R.
通讯作者：
Hayden, Michael R.
影响因子：
3.5
作者：
Huebener, Jeannette;Weber, Jonasz Jeremiasz;Huu Phuc Nguyen
通讯作者：
Huu Phuc Nguyen
影响因子：
5
作者：
Gabr, Moustafa T.;Peccati, Francesca
通讯作者：
Peccati, Francesca
影响因子：
11.2
作者：
Blumen, Sergiu C.;Astord, Stephanie;Viollet, Louis
通讯作者：
Viollet, Louis