Abstract

Herpesviruses are known to encode a number of inhibitors of host cell death, including RIP Homotypic Interaction Motif (RHIM)-containing proteins. Varicella zoster virus (VZV) is a member of the alphaherpesvirus subfamily and is responsible for causing chickenpox and shingles. We have identified a novel viral RHIM in the VZV capsid triplex protein, open reading frame (ORF) 20, that acts as a host cell death inhibitor. Like the human cellular RHIMs in RIPK1 and RIPK3 that stabilise the necrosome in TNF-induced necroptosis, and the viral RHIM in M45 from murine cytomegalovirus that inhibits cell death, the ORF20 RHIM is capable of forming fibrillar functional amyloid complexes. Notably, the ORF20 RHIM forms hybrid amyloid complexes with human ZBP1, a cytoplasmic sensor of viral nucleic acid. Although VZV can inhibit TNF-induced necroptosis, the ORF20 RHIM does not appear to be responsible for this inhibition. In contrast, the ZBP1 pathway is identified as important for VZV infection. Mutation of the ORF20 RHIM renders the virus incapable of efficient spread in ZBP1-expressing HT-29 cells, an effect which can be reversed by the inhibition of caspases. Therefore we conclude that the VZV ORF20 RHIM is important for preventing ZBP1-driven apoptosis during VZV infection, and propose that it mediates this effect by sequestering ZBP1 into decoy amyloid assemblies.

Highlights

  • Viruses have evolved a diverse range of strategies to evade host intrinsic, innate and adaptive immune responses

  • We have identified a novel RIP Homotypic Interaction Motif (RHIM) within the ORF20 protein expressed by Varicella zoster virus (VZV) that forms amyloid-based complexes with human cellular RHIMs

  • Given that in Herpes simplex virus (HSV)-1 and HSV-2 the large subunit of the ribonucleotide reductase contains a functional RHIM [40,41,42, 44], we examined the amino acid sequence of the orthologue in VZV, which is encoded by ORF19

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Summary

Introduction

Viruses have evolved a diverse range of strategies to evade host intrinsic, innate and adaptive immune responses. Members of the Herpesviridae family, Herpes simplex virus (HSV) -1 and human and murine cytomegalovirus (HCMV/MCMV), are masters at manipulating host cell death pathways such as apoptosis and necroptosis, in order to successfully spread and establish latency [1,2,3]. Varicella zoster virus (VZV) causes a significant health burden [4,5,6], the mechanisms employed by VZV to undermine host responses have not been fully elucidated. Primary infection with VZV leads to varicella, commonly known as chickenpox. During this infection the virus establishes latency within sensory neurons, and when VZV-specific T cell immunity wanes, the virus can reactivate to result in herpes zoster (shingles) [7]. Complications arising from VZV reactivation include protracted pain termed post-herpetic neuralgia, encephalitis and VZV vasculopathy (reviewed in [8])

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