VP22 core domain from Herpes simplex virus 1 reveals a surprising structural conservation in both the Alpha- and Gammaherpesvirinae subfamilies

Abstract

The viral tegument is a layer of proteins between the herpesvirus capsid and its outer envelope. According to phylogenetic studies, only a third of these proteins are conserved amongst the three subfamilies (Alpha-, Beta- and Gammaherpesvirinae) of the family Herpesviridae. Although some of these tegument proteins have been studied in more detail, the structure and function of the majority of them are still poorly characterized. VP22 from Herpes simplex virus 1 (subfamily Alphaherpesvirinae) is a highly interacting tegument protein that has been associated with tegument assembly. We have determined the crystal structure of the conserved core domain of VP22, which reveals an elongated dimer with several potential protein–protein interaction regions and a peptide-binding site. The structure provides us with the structural basics to understand the numerous functional mutagenesis studies of VP22 found in the literature. It also establishes an unexpected structural homology to the tegument protein ORF52 from Murid herpesvirus 68 (subfamily Gammaherpesvirinae). Homologues for both VP22 and ORF52 have been identified in their respective subfamilies. Although there is no obvious sequence overlap in the two subfamilies, this structural conservation provides compelling structural evidence for shared ancestry and functional conservation.

Inhibition of cGAS DNA Sensing by a Herpesvirus Virion Protein

“…Viruses other than gammaherpesviruses are conceivably expected to encode cGAS antagonists. A recent study has revealed that the HSV-1 VP22 core domain has limited structural and sequence homology to MHV68 ORF52 (Hew et al, 2015). Because VP22 is also an abundant tegument protein (Spear and Roizman, 1972), it would be interesting to examine whether VP22 can inhibit cGAS, and how other large DNA viruses, such as alpha and beta herpesviruses and poxviruses, overcome cGAS-dependent DNA sensing.…”

A Conserved Leucine Zipper Motif in Gammaherpesvirus ORF52 Is Critical for Distinct Microtubule Rearrangements

“…These effects are most pronounced at late stages of infection during peak levels of virion maturation and egress ( 44 ), and the late lytic protein ORF52, which colocalizes with MT bundles, is both necessary and sufficient to approximate these pronounced changes in MT organization. These cytoskeletal changes are reminiscent of the alterations induced by the overexpression of the structurally related VP22 protein of HSV-1 ( 32 , 45 , 46 ) as well as the otherwise unrelated cellular centrosomal protein Cep57 ( 47 ). Surprisingly, our data also indicate an early function for virion-associated ORF52.…”

“…Although, in our hands, the effect from the overexpression of the KSHV ortholog is significantly less pronounced than that with RRV ORF52, this congruence suggests a likely conservation of function among gammaherpesviruses. Perhaps more remarkably, the tegument protein VP22 of the alphaherpesvirus HSV-1, despite sharing only low levels of regional sequence similarity with the gammaherpesvirus ORF52 orthologs, is a functional ortholog ( 32 ). Specifically, as with RRV ORF52, the ectopic expression of HSV-1 VP22 induces MT bundling and acetylation ( 45 ).…”

“…A structure-based rationalization for the functional similarities has emerged from the X-ray crystallographic analysis of the core portion (residues 174 to 260) of HSV-1 VP22, which adopts a structure highly similar to the core portion (residues 44 to 106) of MHV-68 ORF52; their monomer α carbons align with a root mean square deviation of 2.1 Å ( 31 , 32 ). Each monomer is comprised of a helix-loop-helix followed by a beta strand, which, together, form antiparallel homodimers.…”

“…Transfection experiments demonstrate that the protein, at a minimum, homodimerizes within the cell, and the crystal structure suggests that it forms asymmetric, antiparallel homodimers with the added potential to form antiparallel dimer-dimer homotetramers ( 31 ). Remarkably, the structure of MHV-68 ORF52 is highly reminiscent of that of a portion of the microtubule-interacting alphaherpesvirus protein VP22 of herpes simplex virus 1 (HSV-1), despite the lack of similarity in their primary sequences ( 31 , 32 ).…”