Varicella zoster virus encodes a viral decoy RHIM to inhibit cell death

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 ZBP1expressing 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.

Identification of a Region in the Common Amino-terminal Domain of Hendra Virus P, V, and W Proteins Responsible for Phase Transition and Amyloid Formation

“…A link was established between the formation of amyloid-like assemblies and the membrane-lytic activity of the protein, thereby contributing to shed light on the mechanisms underlying amyloid toxicity. In subsequent studies (reviewed in [ 118 ]), the ability of viral proteins to form fibrillar aggregates was shown to be associated with various functional effects such as the blockade of necroptosis or apoptosis via the formation of hybrid amyloids with host-cell amyloids (RHIM-containing proteins in members of the Herpesviridae family) [ 119 , 120 , 121 ] and the blockade of the stress granule assembly (VP35 from Ebola virus) [ 122 ]). In addition, fibrillar aggregates made of the NSs protein from Rift Valley Fever virus were found to suppress host cell RNA synthesis through host transcription factors’ sequestration [ 123 ]; later on, a functional link was established between the formation of NSs amyloids and virulence, in which NSs fibrils were shown to suppress IFN responses through the silencing of IFN-β expression and the degradation of PKR [ 124 ].…”

“…The fractions of interest were pooled and the sample was then kept in ice until data collection. Samples either at 1 or at 2 mg mL −1 , as obtained upon dilution of the sample from SEC, were incubated at 37 • C and the data were collected at various times points (60,90,120,180,270,300,420,480, and 630 min). Data reductions were performed using the established procedure available at BM29 and buffer background runs were subtracted from sample runs.…”

SARS-CoV-2 proteins regulate inflammatory, thrombotic and diabetic responses in human arterial fibroblasts

“…As viruses require the host cells to survive to produce new viruses, this data would be in agreement with the typical mechanisms that a virus employs. Other groups have shown that under certain conditions viruses can cause reductions in cell viability, but in general reduced cell viability after exposure to viruses is not observed [ 13 ] [ 43 ]. Cell density is a measure of cell proliferation and apoptosis as a function of time.…”

The regulation of necroptosis by post-translational modifications

“…In keeping with its proinflammatory nature, necroptosis has likely evolved as an innate immunity mechanism to complement apoptosis as a means of eliminating pathogens, such as in scenarios where pathogen-encoded proteins block apoptosis [11,12]. The idea that necroptosis arose as an ancestral host defense mechanism is supported by the discovery of viral and bacterial proteins that block necroptosis at various steps of the signaling pathway in animals [13][14][15][16][17][18][19][20][21][22][23], and the recent discovery of convergently-evolved pathway effectors that contribute to plant host defense [24].…”