Yao Hui, Dittmann Meike, Peisley Alys, Hoffmann Hans-Heinrich, Gilmore Rachel H, Schmidt Tobias, Schmidt-Burgk Jonathan, Hornung Veit, Rice Charles M, Hur Sun
Program in Cellular and Molecular Medicine, Children's Hospital Boston, MA 02115, USA.
State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences Nankai University, Tianjin 300071, China.
Mol Cell. 2015 May 7;58(3):541-548. doi: 10.1016/j.molcel.2015.03.014. Epub 2015 Apr 16.
The vertebrate antiviral innate immune system is often considered to consist of two distinct groups of proteins: pattern recognition receptors (PRRs) that detect viral infection and induce the interferon (IFN) signaling, and effectors that directly act against viral replication. Accordingly, previous studies on PRRs, such as RIG-I and MDA5, have primarily focused on their functions in viral double-stranded RNA (dsRNA) detection and consequent antiviral signaling. We report here that both RIG-I and MDA5 efficiently displace viral proteins pre-bound to dsRNA in a manner dependent on their ATP hydrolysis, and that this activity assists a dsRNA-dependent antiviral effector protein, PKR, and allows RIG-I to promote MDA5 signaling. Furthermore, truncated RIG-I/MDA5 lacking the signaling domain, and hence the IFN stimulatory activity, displaces viral proteins and suppresses replication of certain viruses in an ATP-dependent manner. Thus, this study reveals novel "effector-like" functions of RIG-I and MDA5 that challenge the conventional view of PRRs.
检测病毒感染并诱导干扰素（IFN）信号传导的模式识别受体（PRR），以及直接作用于病毒复制的效应蛋白。因此，先前关于PRR（如RIG-I和MDA5）的研究主要集中在它们在病毒双链RNA（dsRNA）检测及随后的抗病毒信号传导中的功能。我们在此报告，RIG-I和MDA5均能以依赖于其ATP水解的方式有效地取代预先结合在dsRNA上的病毒蛋白，并且这种活性有助于一种依赖dsRNA的抗病毒效应蛋白PKR，并使RIG-I促进MDA5信号传导。此外，缺少信号结构域从而缺乏IFN刺激活性的截短型RIG-I/MDA5，以ATP依赖的方式取代病毒蛋白并抑制某些病毒的复制。因此，本研究揭示了RIG-I和MDA5新的“类效应蛋白”功能，这对PRR的传统观点提出了挑战。
