Eukaryotic Stress Granules Are Cleared by Autophagy and Cdc48/VCP Function
Eukaryotic Stress Granules Are Cleared by Autophagy and Cdc48/VCP Function
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DOI：
10.1016/j.cell.2013.05.037
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发表时间：
2013-06-20
期刊：
影响因子：
64.5
通讯作者：
Parker, Roy
中科院分区：
文献类型：
--
作者：
Buchan, J. Ross;Kolaitis, Regina-Maria;Parker, Roy
应激颗粒和P体是非翻译信使核糖核蛋白复合物（mRNP）的保守细胞质聚集体，参与mRNA翻译和衰变的调节，并与胚胎、神经元和某些退行性疾病中的病理性包涵体中的RNP颗粒相关。使用面包酵母，125个基因被确定在遗传筛选，影响P机构和/或应力颗粒的动态。对包括CDC 48等位基因在内的此类突变体的分析提供了证据，即应激颗粒可以通过自噬靶向液泡，这一过程称为颗粒吞噬。此外，哺乳动物细胞中的应激颗粒清除通过抑制自噬或通过含缬氨肽蛋白（VCP）（CDC 48的人类直系同源物）的耗尽或致病性突变而减少。由于VCP的突变使人类易患肌萎缩侧索硬化症、额颞叶变性、包涵体肌病和多系统蛋白病，因此这项工作表明，退行性疾病中出现的应激颗粒相关和致病性RNP颗粒的自噬清除可能对减少其病理学非常重要。
Stress granules and P bodies are conserved cytoplasmic aggregates of nontranslating messenger ribonucleoprotein complexes (mRNPs) implicated in the regulation of mRNA translation and decay and are related to RNP granules in embryos, neurons, and pathological inclusions in some degenerative diseases. Using baker's yeast, 125 genes were identified in a genetic screen that affected the dynamics of P bodies and/or stress granules. Analyses of such mutants, including CDC48 alleles, provide evidence that stress granules can be targeted to the vacuole by autophagy, in a process termed granulophagy. Moreover, stress granule clearance in mammalian cells is reduced by inhibition of autophagy or by depletion or pathogenic mutations in valosin-containing protein (VCP), the human ortholog of CDC48. Because mutations in VCP predispose humans to amyotrophic lateral sclerosis, frontotemporal lobar degeneration, inclusion body myopathy, and multisystem proteinopathy, this work suggests that autophagic clearance of stress granule related and pathogenic RNP granules that arise in degenerative diseases may be important in reducing their pathology.