1. The herpesvirus accessory protein γ134.5 facilitates viral replication by disabling mitochondrial translocation of RIG-I.
- Author
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Liu, Xing, Ma, Yijie, Voss, Kathleen, van Gent, Michiel, Chan, Ying Kai, Gack, Michaela U., Gale, Michael, and He, Bin
- Subjects
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INTERFERON regulatory factors , *VIRAL replication , *HERPES simplex virus , *HERPESVIRUS diseases , *MITOCHONDRIAL proteins - Abstract
RIG-I and MDA5 are cytoplasmic RNA sensors that mediate cell intrinsic immunity against viral pathogens. While it has been well-established that RIG-I and MDA5 recognize RNA viruses, their interactive network with DNA viruses, including herpes simplex virus 1 (HSV-1), remains less clear. Using a combination of RNA-deep sequencing and genetic studies, we show that the γ134.5 gene product, a virus-encoded virulence factor, enables HSV growth by neutralization of RIG-I dependent restriction. When expressed in mammalian cells, HSV-1 γ134.5 targets RIG-I, which cripples cytosolic RNA sensing and subsequently suppresses antiviral gene expression. Rather than inhibition of RIG-I K63-linked ubiquitination, the γ134.5 protein precludes the assembly of RIG-I and cellular chaperone 14-3-3ε into an active complex for mitochondrial translocation. The γ134.5-mediated inhibition of RIG-I-14-3-3ε binding abrogates the access of RIG-I to mitochondrial antiviral-signaling protein (MAVS) and activation of interferon regulatory factor 3. As such, unlike wild type virus HSV-1, a recombinant HSV-1 in which γ134.5 is deleted elicits efficient cytokine induction and replicates poorly, while genetic ablation of RIG-I expression, but not of MDA5 expression, rescues viral growth. Collectively, these findings suggest that viral suppression of cytosolic RNA sensing is a key determinant in the evolutionary arms race of a large DNA virus and its host. Author summary: Host cytosolic RNA sensing has been implicated in the recognition of herpesvirus infection. As such, herpesviruses likely have evolved strategies to escape this host surveillance mechanism; however, molecular insight into antagonism of RNA sensors by herpesviruses remains largely elusive. We show that the γ134.5 protein encoded by herpes simplex virus 1 inactivates the helicase RIG-I that serves as an RNA receptor. Viral γ134.5 hijacks RIG-I and selectively inhibits its engagement with the chaperone protein 14-3-3ε in the cytoplasm of infected cells. Targeting of RIG-I by γ134.5 blocks the cytosol-to-mitochondrial translocation of RIG-I, which ultimately dampens antiviral innate immunity. Finally, depletion of RIG-I enhances the growth of a recombinant HSV-1 in which γ134.5 was deleted. Our work provides insights into viral modulation of intracellular RNA recognition in herpesvirus infection, which in turn may guide the rational development of therapeutic agents. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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