Stress granule assembly is mediated by prion-like aggregation of TIA-1
Stress granule assembly is mediated by prion-like aggregation of TIA-1
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DOI：
10.1091/mbc.e04-08-0715
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发表时间：
2004-12-01
影响因子：
3.3
通讯作者：
Anderson, P
中科院分区：
文献类型：
--
作者：
Gilks, N;Kedersha, N;Anderson, P
TIA-1是一种RNA结合蛋白，其促进应激颗粒（SG）的组装，所述应激颗粒是离散的细胞质内含物，在经历环境应激的细胞中，停滞的翻译起始复合物被动态地募集到所述细胞质内含物中。TIA-1的RNA识别基序与富含谷氨酰胺的朊病毒相关结构域（PRD）相连。缺少PRD结构域的截短突变体不诱导自发性SG，也不被招募到亚砷酸盐诱导的SG中，而PRD形成聚集体，其在低水平表达细胞中被招募到SG中，但在高水平表达细胞中阻止SG组装。TIA-1的PRD表现出朊病毒的许多特征：浓度依赖性聚集，其被分子伴侣热休克蛋白（HSP）70抑制;对蛋白酶消化的抗性; HSP 27、HSP 40和HSP 70的隔离;以及HSP 70的诱导，HSP 70是PRD解聚的反馈调节剂。用酵母朊病毒的聚集结构域SUP 35-NM取代PRD重建SG组装，证实朊病毒结构域可以介导SG的组装。缺乏TIA-1的小鼠胚胎成纤维细胞（MEFs）表现出形成SG的能力受损，尽管它们对亚砷酸盐的反应表现出正常的真核起始因子（eIF）2 α磷酸化。我们的研究结果表明，TIA-1的朊病毒样聚集调节eIF 2 α磷酸化下游的SG形成，以响应压力。
TIA-1 is an RNA binding protein that promotes the assembly of stress granules (SGs), discrete cytoplasmic inclusions into which stalled translation initiation complexes are dynamically recruited in cells subjected to environmental stress. The RNA recognition motifs of TIA-1 are linked to a glutamine-rich prion-related domain (PRD). Truncation mutants lacking the PRD domain do not induce spontaneous SGs and are not recruited to arsenite-induced SGs, whereas the PRD forms aggregates that are recruited to SGs in low-level- expressing cells but prevent SG assembly in high-level-expressing cells. The PRD of TIA-1 exhibits many characteristics of prions: concentration-dependent aggregation that is inhibited by the molecular chaperone heat shock protein (HSP)70; resistance to protease digestion; sequestration of HSP27, HSP40, and HSP70; and induction of HSP70, a feedback regulator of PRD disaggregation. Substitution of the PRD with the aggregation domain of a yeast prion, SUP35-NM, reconstitutes SG assembly, confirming that a prion domain can mediate the assembly of SGs. Mouse embryomic fibroblasts (MEFs) lacking TIA-1 exhibit impaired ability to form SGs, although they exhibit normal phosphorylation of eukaryotic initiation factor (eIF)2alpha in response to arsenite. Our results reveal that prion-like aggregation of TIA-1 regulates SG formation downstream of eIF2alpha phosphorylation in response to stress.