Department of Biology, University of South Carolina, Columbia, SC 29210, U.S.A.
Biochem J. 2021 Feb 12;478(3):493-510. doi: 10.1042/BCJ20200987.
An integral aspect of innate immunity is the ability to detect foreign molecules of viral origin to initiate antiviral signaling via pattern recognition receptors (PRRs). One such receptor is the RNA helicase retinoic acid inducible gene 1 (RIG-I), which detects and is activated by 5'triphosphate uncapped double stranded RNA (dsRNA) as well as the cytoplasmic viral mimic dsRNA polyI:C. Once activated, RIG-I's CARD domains oligomerize and initiate downstream signaling via mitochondrial antiviral signaling protein (MAVS), ultimately inducing interferon (IFN) production. Another dsRNA binding protein PACT, originally identified as the cellular protein activator of dsRNA-activated protein kinase (PKR), is known to enhance RIG-I signaling in response to polyI:C treatment, in part by stimulating RIG-I's ATPase and helicase activities. TAR-RNA-binding protein (TRBP), which is ∼45% homologous to PACT, inhibits PKR signaling by binding to PKR as well as by sequestration of its' activators, dsRNA and PACT. Despite the extensive homology and similar structure of PACT and TRBP, the role of TRBP has not been explored much in RIG-I signaling. This work focuses on the effect of TRBP on RIG-I signaling and IFN production. Our results indicate that TRBP acts as an inhibitor of RIG-I signaling in a PACT- and PKR-independent manner. Surprisingly, this inhibition is independent of TRBP's post-translational modifications that are important for other signaling functions of TRBP, but TRBP's dsRNA-binding ability is essential. Our work has major implications on viral susceptibility, disease progression, and antiviral immunity as it demonstrates the regulatory interplay between PACT and TRBP IFN production.
先天免疫的一个重要方面是能够检测病毒来源的外来分子，通过模式识别受体 (PRRs) 启动抗病毒信号。这样的受体之一是 RNA 解旋酶维甲酸诱导基因 1 (RIG-I)，它可以检测到并被 5'三磷酸无帽双链 RNA (dsRNA) 以及细胞质病毒类似物 dsRNA 聚肌苷酸激活。一旦被激活，RIG-I 的 CARD 结构域寡聚化，并通过线粒体抗病毒信号蛋白 (MAVS) 启动下游信号，最终诱导干扰素 (IFN) 的产生。另一种 dsRNA 结合蛋白 PACT，最初被鉴定为 dsRNA 激活蛋白激酶 (PKR) 的细胞蛋白激活剂，已知可增强 RIG-I 信号对 polyI:C 处理的反应，部分原因是刺激 RIG-I 的 ATP 酶和解旋酶活性。TAR-RNA 结合蛋白 (TRBP) 与 PACT 具有约 45%的同源性，通过与 PKR 结合以及隔离其激活剂 dsRNA 和 PACT 来抑制 PKR 信号。尽管 PACT 和 TRBP 具有广泛的同源性和相似的结构，但 TRBP 在 RIG-I 信号中的作用尚未得到充分探索。这项工作重点研究了 TRBP 对 RIG-I 信号和 IFN 产生的影响。我们的结果表明，TRBP 以 PACT 和 PKR 独立的方式充当 RIG-I 信号的抑制剂。令人惊讶的是，这种抑制作用独立于 TRBP 的翻译后修饰，这些修饰对于 TRBP 的其他信号功能很重要，但 TRBP 的 dsRNA 结合能力是必需的。我们的工作对病毒易感性、疾病进展和抗病毒免疫具有重要意义，因为它证明了 PACT 和 TRBP IFN 产生之间的调节相互作用。
