CCT complex restricts neuropathogenic protein aggregation via autophagy.
CCT complex restricts neuropathogenic protein aggregation via autophagy.
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CCT 复合物通过自噬限制神经病原蛋白聚集。
DOI：
10.1038/ncomms13821
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发表时间：
2016-12-08
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
异常蛋白聚集受多种伴侣蛋白控制，包括CCT（含TCP-1的伴侣蛋白）/TCP-1/TRiC。突变的CCT4/5亚基引起感觉神经病变，并且在阿尔茨海默病中CCT5表达降低。在这里，我们发现CCT的完整性对于果蝇细胞中的自噬体降解是必不可少的，这种现象是由肌动蛋白细胞骨架精心策划的。当自噬通量因单个CCT亚基受损而减少时，各种疾病相关的自噬底物积累和聚集。在CCT2/5/7缺失后，突变型亨廷顿蛋白、ATXN3或p62等蛋白的聚集主要依赖于自噬，并且在自噬缺陷细胞/生物体中，随着CCT敲低，这些蛋白的聚集不会进一步增加，这令人惊讶地表明，CCT活性丧失对突变型ATXN3或亨廷顿蛋白寡聚/聚集的影响主要是自噬抑制的结果，而不是这些蛋白的生理抗聚集活性丧失。因此，我们的研究结果揭示了蛋白质平衡网络的两个关键组成部分之间的重要伙伴关系，并涉及CCT复合物活性受损疾病的自噬缺陷。CCT复合体是伴侣机制中的关键角色，与亨廷顿氏病有关。Pavel等人表明，CCT2/5/7在自噬体降解中也起着重要作用，CCT2/5/7耗损后蛋白质聚集主要是自噬受损的结果。
Aberrant protein aggregation is controlled by various chaperones, including CCT (chaperonin containing TCP-1)/TCP-1/TRiC. Mutated CCT4/5 subunits cause sensory neuropathy and CCT5 expression is decreased in Alzheimer's disease. Here, we show that CCT integrity is essential for autophagosome degradation in cells or Drosophila and this phenomenon is orchestrated by the actin cytoskeleton. When autophagic flux is reduced by compromise of individual CCT subunits, various disease-relevant autophagy substrates accumulate and aggregate. The aggregation of proteins like mutant huntingtin, ATXN3 or p62 after CCT2/5/7 depletion is predominantly autophagy dependent, and does not further increase with CCT knockdown in autophagy-defective cells/organisms, implying surprisingly that the effect of loss-of-CCT activity on mutant ATXN3 or huntingtin oligomerization/aggregation is primarily a consequence of autophagy inhibition rather than loss of physiological anti-aggregation activity for these proteins. Thus, our findings reveal an essential partnership between two key components of the proteostasis network and implicate autophagy defects in diseases with compromised CCT complex activity. The CCT complex, a key player in the chaperone machinery, has been implicated in Huntington's disease. Pavel et al. show that CCT2/5/7 also play an essential role in autophagosome degradation, and that the aggregation of proteins upon CCT2/5/7 depletion is primarily a consequence of impaired autophagy.
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影响因子：
9.2
作者：
Bright, Nicholas A.;Davis, Luther J.;Luzio, J. Paul
通讯作者：
Luzio, J. Paul
影响因子：
14.8
作者：
Jimenez-Sanchez M;Lam W;Hannus M;Sönnichsen B;Imarisio S;Fleming A;Tarditi A;Menzies F;Dami TE;Xu C;Gonzalez-Couto E;Lazzeroni G;Heitz F;Diamanti D;Massai L;Satagopam VP;Marconi G;Caramelli C;Nencini A;Andreini M;Sardone GL;Caradonna NP;Porcari V;Scali C;Schneider R;Pollio G;O'Kane CJ;Caricasole A;Rubinsztein DC
通讯作者：
Rubinsztein DC
HSP90-TAU复合物揭示了伴侣作用特异性的分子基础。
影响因子：
64.5
作者：
Karagöz GE;Duarte AM;Akoury E;Ippel H;Biernat J;Morán Luengo T;Radli M;Didenko T;Nordhues BA;Veprintsev DB;Dickey CA;Mandelkow E;Zweckstetter M;Boelens R;Madl T;Rüdiger SG
通讯作者：
Rüdiger SG
影响因子：
8.8
作者：
Brehme M;Voisine C;Rolland T;Wachi S;Soper JH;Zhu Y;Orton K;Villella A;Garza D;Vidal M;Ge H;Morimoto RI
通讯作者：
Morimoto RI
p62/SQSTM1形成自噬降解的蛋白质聚集体，并对亨廷顿蛋白诱导的细胞死亡具有保护作用。
影响因子：
7.8
作者：
Bjorkoy, Geir;Lamark, Trond;Brech, Andreas;Outzen, Heidi;Perander, Maria;Overvatn, Aud;Stenmark, Harald;Johansen, Terje
通讯作者：
Johansen, Terje