The herpesvirus accessory protein γ134.5 facilitates viral replication by disabling mitochondrial translocation of RIG-I.

Xing Liu,Yijie Ma,Michaela U Gack,Kathleen Voss,Ying Kai Chan,Michiel Van Gent,Michael Gale,Bin He,Philip E Pellett

doi:10.1371/journal.ppat.1009446

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.

Highlights

The RIG-I-like receptors (RLR), which include RIG-I, MDA5, and LGP2, are best known to recognize RNA viruses [1,2]
Host cytosolic RNA sensing has been implicated in the recognition of herpesvirus infection
We show that the γ134.5 protein encoded by herpes simplex virus

Summary

Introduction

The RIG-I-like receptors (RLR), which include RIG-I (retinoic acid-inducible gene-I), MDA5 (melanoma differentiation-associated gene 5), and LGP2 (laboratory of genetics and physiology 2), are best known to recognize RNA viruses [1,2]. Whereas RIG-I is in a closed, inactive conformation in uninfected cells, it adopts conformational changes upon activation by RNA viruses; this, triggers RIG-I dephosphorylation, its K63-linked ubiquitination and mitochondrial translocation [2,4]. In this process, protein phosphatase 1, the ubiquitin ligases TRIM25 and Riplet, and the chaperone protein 14-3-3ε cooperatively allow RIG-I to active downstream targets, resulting in an antiviral state [5,6,7,8]. Herpes simplex virus 1 (HSV-1) triggers RIG-I activation via RNA polymerase III that generates 5’-ppp RNA species, including host 5S ribosomal pseudogene transcripts due to virus-mediated depletion of specific RNA-binding proteins [15,16]

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Conclusion