Abstract
Nuclear egress is a regulated process shared by α-, β- and γ-herpesviruses. The core nuclear egress complex (NEC) is composed of the membrane-anchored protein homologs of human cytomegalovirus (HCMV) pUL50, murine cytomegalovirus (MCMV) pM50, Epstein–Barr virus (EBV) BFRF1 or varicella zoster virus (VZV) Orf24, which interact with the autologous NEC partners pUL53, pM53, BFLF2 or Orf27, respectively. Their recruitment of additional proteins leads to the assembly of a multicomponent NEC, coordinately regulating viral nucleocytoplasmic capsid egress. Here, the functionality of VZV, HCMV, MCMV and EBV core NECs was investigated by coimmunoprecipitation and confocal imaging analyses. Furthermore, a recombinant MCMV, harboring a replacement of ORF M50 by UL50, was analyzed both in vitro and in vivo. In essence, core NEC interactions were strictly limited to autologous NEC pairs and only included one measurable nonautologous interaction between the homologs of HCMV and MCMV. A comparative analysis of MCMV-WT versus MCMV-UL50-infected murine fibroblasts revealed almost identical phenotypes on the levels of protein and genomic replication kinetics. In infected BALB/c mice, virus spread to lung and other organs was found comparable between these viruses, thus stating functional complementarity. In conclusion, our study underlines that herpesviral core NEC proteins are functionally conserved regarding complementarity of core NEC interactions, which were found either virus-specific or restricted within subfamilies.
Highlights
Herpesviruses are distributed worldwide and are classified into three subfamilies according to their pathogenicity, cell tropism and proliferative characteristics: α, β- and γ-herpesviruses.All herpesviruses persist after primary infection and can reactivate from this latency
We reported the first structure of γ-herpesviral core nuclear egress complex (NEC), namely the 1.75 Å structure of Epstein–Barr virus (EBV) BFRF1-BFLF2, as well as an increased resolution 1.48 Å structure of human cytomegalovirus (HCMV) pUL50-pUL53 [16]
This study provides novel insights into the interaction properties of varicella zoster virus (VZV), HCMV, murine cytomegalovirus (MCMV) and core NECs, in particular into their biochemical properties of core NEC binding in vitro and in vivo, EBV core NECs, in particular into their biochemical properties of core NEC binding in vitro and in and their intranuclear rim recruitment and association with additional regularly factors
Summary
Herpesviruses are distributed worldwide and are classified into three subfamilies according to their pathogenicity, cell tropism and proliferative characteristics: α-, β- and γ-herpesviruses. All herpesviruses persist after primary infection and can reactivate from this latency. The varicella zoster virus (VZV), a human representative of α-herpesviruses, causes chickenpox and persists in neurons of various ganglions leading to herpes zoster after reactivation. Human cytomegalovirus (HCMV, β-herpesvirus) infection of immunocompetent individuals is mostly asymptomatic and only rarely induces symptoms whereas in immunosuppressed individuals (e.g., transplant recipients or acquired immunodeficiency syndrome (AIDS) patients) infection can cause severe life-threatening symptoms. HCMV is the main cause of non-genetic congenital malformations and spontaneous abortions. The most common model in use for studying the principles of β-herpesviral infection and pathogenesis is the murine cytomegalovirus (MCMV).
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