Department of Biological Sciences, University of South Carolina, Columbia, SC, 29208, USA.
Sci Rep. 2018 Jan 18;8(1):1020. doi: 10.1038/s41598-018-19360-8.
Transactivation response element RNA-binding protein (TRBP or TARBP2) initially identified to play an important role in human immunodeficiency virus (HIV) replication also has emerged as a regulator of microRNA biogenesis. In addition, TRBP functions in signaling pathways by negatively regulating the interferon-induced double-stranded RNA (dsRNA)-activated protein kinase (PKR) during viral infections and cell stress. During cellular stress, PKR is activated and phosphorylates the α subunit of the eukaryotic translation factor eIF2, leading to the cessation of general protein synthesis. TRBP inhibits PKR activity by direct interaction as well as by binding to PKR's two known activators, dsRNA and PACT, thus preventing their interaction with PKR. In this study, we demonstrate for the first time that TRBP is phosphorylated in response to oxidative stress and upon phosphorylation, inhibits PKR more efficiently promoting cell survival. These results establish that PKR regulation through stress-induced TRBP phosphorylation is an important mechanism ensuring cellular recovery and preventing apoptosis due to sustained PKR activation.
反式激活反应元件 RNA 结合蛋白（TRBP 或 TARBP2）最初被鉴定在人类免疫缺陷病毒（HIV）复制中发挥重要作用，它也已成为 microRNA 生物发生的调节剂。此外，TRBP 通过在病毒感染和细胞应激期间负调控干扰素诱导的双链 RNA（dsRNA）激活的蛋白激酶（PKR）在信号通路中发挥作用。在细胞应激期间，PKR 被激活并磷酸化真核翻译因子 eIF2 的 α 亚基，导致一般蛋白质合成停止。TRBP 通过直接相互作用以及与 PKR 的两个已知激活剂 dsRNA 和 PACT 结合来抑制 PKR 活性，从而阻止它们与 PKR 的相互作用。在这项研究中，我们首次证明 TRBP 可响应氧化应激而发生磷酸化，并且磷酸化后可更有效地抑制 PKR，从而促进细胞存活。这些结果表明，通过应激诱导的 TRBP 磷酸化来调节 PKR 是一种重要的机制，可确保细胞恢复并防止由于 PKR 持续激活而导致的细胞凋亡。
