Altered organization of the intermediate filament cytoskeleton and relocalization of proteostasis modulators in cells lacking the ataxia protein sacsin.
Altered organization of the intermediate filament cytoskeleton and relocalization of proteostasis modulators in cells lacking the ataxia protein sacsin.
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DOI：
10.1093/hmg/ddx197
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发表时间：
2017-08-15
影响因子：
3.5
通讯作者：
Chapple JP
中科院分区：
文献类型：
--
作者：
Duncan EJ;Larivière R;Bradshaw TY;Longo F;Sgarioto N;Hayes MJ;Romano LEL;Nethisinghe S;Giunti P;Bruntraeger MB;Durham HD;Brais B;Maltecca F;Gentil BJ;Chapple JP
常染色体隐性夏勒瓦-萨格奈痉挛性共济失调 (ARSACS) 是由编码 520 kDa 蛋白质 sacsin 的 SACS 基因突变引起的。尽管 sacsin 的生理作用很大程度上未知，但其序列域表明其具有分子伴侣或蛋白质质量控制功能。其损失的后果包括神经丝网络异常，特别是核周和树突神经丝的积累和成束。为了研究 sacsin 的丢失是否更广泛地影响中间丝，分析了 ARSACS 患者成纤维细胞和 sacsin 表达减少的细胞中波形蛋白的分布。波形蛋白丝在核周异常聚集，有时呈笼状外观，发生在 sacsin 缺陷细胞中。线粒体和其他细胞器被转移到波形蛋白积累的外围。波形蛋白网络的重组发生在体外压力条件下，包括当错误折叠的蛋白质积累时。在 ARSACS 患者中，成纤维细胞 HSP70、泛素以及自噬溶酶体途径蛋白 Lamp2 和 p62 重新定位到波形蛋白积聚区域。泛素化蛋白没有总体增加，表明泛素-蛋白酶体系统没有受损。有证据表明自噬-溶酶体途径发生了改变。具体来说，在 ARSACS HDF 中，Lamp2 的细胞水平升高，而在自噬中降解的 p62 水平降低。此外，在饥饿条件下，ARSACS HDF 的自噬通量增加。这些数据表明，sacsin 的丢失会影响多种细胞类型中中间丝的组织，从而影响其他细胞器的细胞分布并影响自噬活性。
Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is caused by mutations in the gene SACS, encoding the 520 kDa protein sacsin. Although sacsin’s physiological role is largely unknown, its sequence domains suggest a molecular chaperone or protein quality control function. Consequences of its loss include neurofilament network abnormalities, specifically accumulation and bundling of perikaryal and dendritic neurofilaments. To investigate if loss of sacsin affects intermediate filaments more generally, the distribution of vimentin was analysed in ARSACS patient fibroblasts and in cells where sacsin expression was reduced. Abnormal perinuclear accumulation of vimentin filaments, which sometimes had a cage-like appearance, occurred in sacsin-deficient cells. Mitochondria and other organelles were displaced to the periphery of vimentin accumulations. Reorganization of the vimentin network occurs in vitro under stress conditions, including when misfolded proteins accumulate. In ARSACS patient fibroblasts HSP70, ubiquitin and the autophagy-lysosome pathway proteins Lamp2 and p62 relocalized to the area of the vimentin accumulation. There was no overall increase in ubiquitinated proteins, suggesting the ubiquitin–proteasome system was not impaired. There was evidence for alterations in the autophagy–lysosome pathway. Specifically, in ARSACS HDFs cellular levels of Lamp2 were elevated while levels of p62, which is degraded in autophagy, were decreased. Moreover, autophagic flux was increased in ARSACS HDFs under starvation conditions. These data show that loss of sacsin effects the organization of intermediate filaments in multiple cell types, which impacts the cellular distribution of other organelles and influences autophagic activity.
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影响因子：
3.5
作者：
Parfitt DA;Michael GJ;Vermeulen EG;Prodromou NV;Webb TR;Gallo JM;Cheetham ME;Nicoll WS;Blatch GL;Chapple JP
通讯作者：
Chapple JP
影响因子：
3.5
作者：
Chen H;Chan DC
通讯作者：
Chan DC
影响因子：
6
作者：
Criscuolo, Chiara;Procaccini, C.;Santorelli, F. M.
通讯作者：
Santorelli, F. M.
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
影响因子：
3.5
作者：
Bradshaw TY;Romano LE;Duncan EJ;Nethisinghe S;Abeti R;Michael GJ;Giunti P;Vermeer S;Chapple JP
通讯作者：
Chapple JP