1. The herpesvirus accessory protein γ134.5 facilitates viral replication by disabling mitochondrial translocation of RIG-I.
- Author
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Liu X, Ma Y, Voss K, van Gent M, Chan YK, Gack MU, Gale M Jr, and He B
- Subjects
- Animals, Chlorocebus aethiops, Fibroblasts metabolism, HEK293 Cells, Herpesvirus 1, Human metabolism, Humans, Mitochondria metabolism, Protein Transport physiology, Vero Cells, DEAD Box Protein 58 metabolism, Herpes Simplex metabolism, Herpesvirus 1, Human pathogenicity, Receptors, Immunologic metabolism, Viral Proteins metabolism, Virus Replication physiology
- 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., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2021
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