Abstract
All gamma-herpesviruses encode at least one homolog of the cellular enzyme formyl-glycineamide-phosphoribosyl-amidotransferase. Murid herpesvirus-4 (MuHV-4) encodes 3 (ORFs 75a, 75b and 75c), suggesting that at least some copies have acquired new functions. Here we show that the corresponding proteins are all present in virions and localize to infected cell nuclei. Despite these common features, ORFs 75a and 75b did not substitute functionally for a lack of ORF75c, as ORF75c virus knockouts were severely impaired for lytic replication in vitro and for host colonization in vivo. They showed 2 defects: incoming capsids failed to migrate to the nuclear margin following membrane fusion, and genomes that did reach the nucleus failed to initiate normal gene expression. The latter defect was associated with a failure of in-coming virions to disassemble PML bodies. The capsid transport deficit seemed to be functionally more important, since ORF75c− MuHV-4 infected both PML+ and PML− cells poorly. The original host enzyme has therefore evolved into a set of distinct and multi-functional viral tegument proteins. One important function is moving incoming capsids to the nuclear margin for viral genome delivery.
Highlights
Enzymes of DNA metabolism feature prominently among the host genes captured by herpesviruses
All sequenced gamma-herpesviruses share a homolog of the cellular formyl-glycineamide-phosphoribosyl-amidotransferase (FGARAT or FGAM synthase), which catalyzes the fourth of ten steps in de novo purine biosynthesis [3]
We show further that ORF75c-deficient Murid Herpesvirus-4 (MuHV-4) remains capable of lytic replication, it was severely attenuated relative to the wild-type
Summary
Enzymes of DNA metabolism feature prominently among the host genes captured by herpesviruses. The cytomegalovirus ribonucleotide reductase homolog no longer functions as such [1] and host dCTPase homologs captured by gamma-herpesviruses are no longer dCTPases [2]. All sequenced gamma-herpesviruses share a homolog of the cellular formyl-glycineamide-phosphoribosyl-amidotransferase (FGARAT or FGAM synthase), which catalyzes the fourth of ten steps in de novo purine biosynthesis [3]. The viral homologs are more closely related to each-other than any is to the cellular gene, implying a single capture event early in gamma-herpesvirus evolution. Analysis of Epstein-Barr virus lacking its (single) ORF75 homolog, BNRF1, found no defect in DNA replication after reactivation, but a 20-fold reduction in B cell transformation by the progeny virions [7]. Rather than functioning in viral DNA replication, BNRF1 appeared to function late in virion entry
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