Chronic starvation induces noncanonical pro-death stress granules
Chronic starvation induces noncanonical pro-death stress granules
复制标题
DOI：
10.1242/jcs.220244
复制
发表时间：
2018-10-01
影响因子：
4
通讯作者：
Neilson, Joel R.
中科院分区：
文献类型：
--
作者：
Reineke, Lucas C.;Cheema, Shebna A.;Neilson, Joel R.
应激颗粒（SG）在抑制蛋白质合成的应激诱导条件下组装，包括eIF2 α磷酸化、RNA解旋酶eIF4a蛋白抑制或mTORC 1失活。经典定义的SG由翻译起始因子、40S核糖体、RNA结合蛋白和poly（A）（+）mRNA组成。因此，它们代表了储存mRNA和调节其翻译的重要隔室。新兴的SGs研究表明，这些结构可能会促进细胞在不同疾病状态下的存活。然而，许多关于SG形成和功能的工作采用急性应激条件，这可能无法准确反映人类疾病中表现出的慢性应激。在这里，我们使用长时间的营养饥饿模型和研究SG的形成和功能，在慢性应激过程中，在人类细胞系和小鼠胚胎成纤维细胞。令人惊讶的是，我们发现在慢性营养饥饿下形成的SG缺乏40S核糖体，不会主动与细胞质池交换其组成成分并促进细胞死亡。我们将这些SGs命名为饥饿诱导SGs（stSGs）。我们的研究结果表明，在长期营养饥饿应激的背景下，SG组装和功能显着不同的急性应激条件下所描述的。
Stress granules (SGs) assemble under stress-induced conditions that inhibit protein synthesis, including phosphorylation of eIF2 alpha, inhibition of the RNA helicase eIF4a proteins or inactivation of mTORC1. Classically defined SGs are composed of translation initiation factors, 40S ribosomes, RNA-binding proteins and poly(A)(+) mRNAs. As such, they represent an important compartment for storage of mRNAs and regulation of their translation. Emerging work on SGs indicates that these structures might promote cellular survival in diverse disease states. Yet, much work on SG formation and function employs acute stress conditions, which might not accurately reflect the chronic stresses that manifest in human disease. Here, we used prolonged nutrient starvation to model and investigate SG formation and function during chronic stress in a human cell line and mouse embryonic fibroblasts. Surprisingly, we found that SGs that form under chronic nutrient starvation lack 40S ribosomes, do not actively exchange their constituent components with cytoplasmic pools and promote cell death. We named these SGs starvation-induced SGs (stSGs). Our results on stSGs imply that SG assembly and function in the context of prolonged nutrient starvation stress differ significantly from what has been described for acute stress conditions.