Abstract

ABSTRACTThe tegument of herpesviruses is a highly complex structural layer between the nucleocapsid and the envelope of virions. Tegument proteins play both structural and regulatory functions during replication and spread, but the interactions and functions of many of these proteins are poorly understood. Here we focus on two tegument proteins from herpes simplex virus 1 (HSV-1), pUL7 and pUL51, which have homologues in all other herpesviruses. We have now identified that HSV-1 pUL7 and pUL51 form a stable and direct protein-protein interaction, their expression levels rely on the presence of each other, and they function as a complex in infected cells. We demonstrate that expression of the pUL7-pUL51 complex is important for efficient HSV-1 assembly and plaque formation. Furthermore, we also discovered that the pUL7-pUL51 complex localizes to focal adhesions at the plasma membrane in both infected cells and in the absence of other viral proteins. The expression of pUL7-pUL51 is important to stabilize focal adhesions and maintain cell morphology in infected cells and cells infected with viruses lacking pUL7 and/or pUL51 round up more rapidly than cells infected with wild-type HSV-1. Our data suggest that, in addition to the previously reported functions in virus assembly and spread for pUL51, the pUL7-pUL51 complex is important for maintaining the attachment of infected cells to their surroundings through modulating the activity of focal adhesion complexes.IMPORTANCE Herpesviridae is a large family of highly successful human and animal pathogens. Virions of these viruses are composed of many different proteins, most of which are contained within the tegument, a complex structural layer between the nucleocapsid and the envelope within virus particles. Tegument proteins have important roles in assembling virus particles as well as modifying host cells to promote virus replication and spread. However, little is known about the function of many tegument proteins during virus replication. Our study focuses on two tegument proteins from herpes simplex virus 1 that are conserved in all herpesviruses: pUL7 and pUL51. We demonstrate that these proteins directly interact and form a functional complex that is important for both virus assembly and modulation of host cell morphology. Further, we identify for the first time that these conserved herpesvirus tegument proteins localize to focal adhesions in addition to cytoplasmic juxtanuclear membranes within infected cells.

Highlights

  • The tegument of herpesviruses is a highly complex structural layer between the nucleocapsid and the envelope of virions

  • Our results suggest that these proteins may form higher-molecular-weight complexes, because glutathione S-transferase (GST)-pUL51 pulled down green fluorescent protein (GFP)-pUL51 and GST-pUL7 pulled down GFP-pUL7, albeit with weaker signals than detected for the pUL7-pUL51 interactions

  • Key factors in controlling virion assembly are likely to be the major structural proteins, such as VP16, VP13/14, and VP22, as well as tegument proteins that directly interact with capsids, such as pUL36

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Summary

Introduction

The tegument of herpesviruses is a highly complex structural layer between the nucleocapsid and the envelope of virions. IMPORTANCE Herpesviridae is a large family of highly successful human and animal pathogens Virions of these viruses are composed of many different proteins, most of which are contained within the tegument, a complex structural layer between the nucleocapsid and the envelope within virus particles. Our study focuses on two tegument proteins from herpes simplex virus 1 that are conserved in all herpesviruses: pUL7 and pUL51 We demonstrate that these proteins directly interact and form a functional complex that is important for both virus assembly and modulation of host cell morphology. Tegument proteins facilitate virus replication by regulating gene transcription, shutting off cellular protein synthesis, interacting with cellular transport machinery, and undermining innate immune responses (reviewed in reference 4) They provide a scaffold for viral particle assembly, creating a network of interactions connecting the capsid with the viral envelope proteins [5, 6]. Recent advances in fluorescence microscopy imaging are starting to unravel the details of tegument organization [7, 8]

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