Aggresomes: a cellular response to misfolded proteins.
Aggresomes: a cellular response to misfolded proteins.
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DOI：
10.1083/jcb.143.7.1883
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发表时间：
1998-12-28
期刊：
影响因子：
--
通讯作者：
Kopito RR
中科院分区：
文献类型：
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作者：
Johnston JA;Ward CL;Kopito RR
错误折叠的蛋白质聚集体在细胞内沉积为富含泛素的细胞质包涵体与许多疾病的发病机制有关。尽管存在识别和降解错误折叠蛋白质的细胞机制，但这些聚集体为何形成以及它们如何被转运至细胞质包涵体尚不清楚。我们研究了囊性纤维化跨膜传导调节因子（CFTR）在细胞内的命运，CFTR是一种折叠效率低下的整合膜蛋白，可通过细胞质泛素 - 蛋白酶体途径降解。在转染的人胚胎肾细胞或中国仓鼠卵巢细胞中，蛋白酶体活性的过度表达或抑制导致稳定的、高分子量、耐去污剂、多泛素化形式的CFTR积聚。通过免疫荧光和免疫金标记的透射电子显微镜技术，我们证明未降解的CFTR分子积聚在一种独特的中心粒周围结构中，我们将其称为聚集体（aggresome）。聚集体形成的同时伴随着中间丝蛋白波形蛋白的重新分布，形成一个笼子围绕着中心粒周围由聚集的、泛素化蛋白质构成的核心。微管的破坏会阻止聚集体的形成。同样，蛋白酶体功能的抑制也阻止了未组装的早老素 - 1分子的降解，导致它们聚集并沉积在聚集体中。这些数据使我们提出，当易于聚集的错误折叠蛋白质的产生超过蛋白酶体的能力时，聚集体的形成是细胞的一种普遍反应。
Intracellular deposition of misfolded protein aggregates into ubiquitin-rich cytoplasmic inclusions is linked to the pathogenesis of many diseases. Why these aggregates form despite the existence of cellular machinery to recognize and degrade misfolded protein and how they are delivered to cytoplasmic inclusions are not known. We have investigated the intracellular fate of cystic fibrosis transmembrane conductance regulator (CFTR), an inefficiently folded integral membrane protein which is degraded by the cytoplasmic ubiquitin-proteasome pathway. Overexpression or inhibition of proteasome activity in transfected human embryonic kidney or Chinese hamster ovary cells led to the accumulation of stable, high molecular weight, detergent-insoluble, multiubiquitinated forms of CFTR. Using immunofluorescence and transmission electron microscopy with immunogold labeling, we demonstrate that undegraded CFTR molecules accumulate at a distinct pericentriolar structure which we have termed the aggresome. Aggresome formation is accompanied by redistribution of the intermediate filament protein vimentin to form a cage surrounding a pericentriolar core of aggregated, ubiquitinated protein. Disruption of microtubules blocks the formation of aggresomes. Similarly, inhibition of proteasome function also prevented the degradation of unassembled presenilin-1 molecules leading to their aggregation and deposition in aggresomes. These data lead us to propose that aggresome formation is a general response of cells which occurs when the capacity of the proteasome is exceeded by the production of aggregation-prone misfolded proteins.