Department of Cellular & Molecular Medicine, College of Medicine, Chosun University, Gwangju, 61452, Republic of Korea.
Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, 21205, USA.
Biochem Biophys Res Commun. 2022 Jan 15;588:125-132. doi: 10.1016/j.bbrc.2021.12.049. Epub 2021 Dec 18.
Stress granules (SGs) are cytoplasmic biomolecular condensates that are formed against a variety of stress conditions when translation initiation is perturbed. SGs form through the weak protein-protein, protein-RNA, and RNA-RNA interactions, as well as through the intrinsically disordered domains and post-translation modifications within RNA binding proteins (RBPs). SGs are known to contribute to cell survivability by minimizing the stress-induced damage to the cells by delaying the activation of apoptosis. Here, we find that dihydrocapsaicin (DHC), an analogue of capsaicin, is a SG inducer that promotes polysome disassembly and reduces global protein translation via phosphorylation of eIF2α. DHC-mediated SG assembly is controlled by the phosphorylation of eIF2α at serine 51 position and is controlled by all four eIF2α stress kinases (i.e., HRI, PKR, PERK, and GCN2) with HRI showing maximal effect. We demonstrate that DHC is a bonafide compound that induces SG assembly, disassembles polysome, phosphorylates eIF2α in an HRI dependent manner, and thereby arrest global translation. Together, our results suggest that DHC is a novel SG inducer and an alternate to sodium arsenite to study SG dynamics.
应激颗粒（SGs）是细胞质生物分子凝聚物，当翻译起始受到干扰时，会在各种应激条件下形成。SGs 通过弱的蛋白质-蛋白质、蛋白质-RNA 和 RNA-RNA 相互作用，以及 RNA 结合蛋白（RBPs）内的固有无序结构域和翻译后修饰形成。已知 SGs 通过延迟细胞凋亡的激活来减轻应激对细胞的损伤，从而有助于细胞存活。在这里，我们发现二氢辣椒素（DHC），辣椒素的类似物，是一种 SG 诱导剂，通过磷酸化 eIF2α 促进多核糖体解聚并减少全局蛋白质翻译。DHC 介导的 SG 组装受 eIF2α 丝氨酸 51 位磷酸化的控制，由四种 eIF2α 应激激酶（即 HRI、PKR、PERK 和 GCN2）控制，其中 HRI 作用最大。我们证明 DHC 是一种诱导 SG 组装、解聚多核糖体、依赖 HRI 磷酸化 eIF2α 的真正化合物，从而阻止全局翻译。总之，我们的结果表明，DHC 是一种新型的 SG 诱导剂，可替代亚砷酸钠用于研究 SG 动力学。
