Herpes Simplex Virus 1 Recruits CD98 Heavy Chain and β1 Integrin to the Nuclear Membrane for Viral De-Envelopment

J Virol. 2015 Aug;89(15):7799-812. doi: 10.1128/JVI.00741-15. Epub 2015 May 20.

Abstract

Herpesviruses have evolved a unique mechanism for nucleocytoplasmic transport of nascent nucleocapsids: the nucleocapsids bud through the inner nuclear membrane (INM; primary envelopment), and the enveloped nucleocapsids then fuse with the outer nuclear membrane (de-envelopment). Little is known about the molecular mechanism of herpesviral de-envelopment. We show here that the knockdown of both CD98 heavy chain (CD98hc) and its binding partner β1 integrin induced membranous structures containing enveloped herpes simplex virus 1 (HSV-1) virions that are invaginations of the INM into the nucleoplasm and induced aberrant accumulation of enveloped virions in the perinuclear space and in the invagination structures. These effects were similar to those of the previously reported mutation(s) in HSV-1 proteins gB, gH, UL31, and/or Us3, which were shown here to form a complex(es) with CD98hc in HSV-1-infected cells. These results suggested that cellular proteins CD98hc and β1 integrin synergistically or independently regulated HSV-1 de-envelopment, probably by interacting directly and/or indirectly with these HSV-1 proteins.

Importance: Certain cellular and viral macromolecular complexes, such as Drosophila large ribonucleoprotein complexes and herpesvirus nucleocapsids, utilize a unique vesicle-mediated nucleocytoplasmic transport: the complexes acquire primary envelopes by budding through the inner nuclear membrane into the space between the inner and outer nuclear membranes (primary envelopment), and the enveloped complexes then fuse with the outer nuclear membrane to release de-enveloped complexes into the cytoplasm (de-envelopment). However, there is a lack of information on the molecular mechanism of de-envelopment fusion. We report here that HSV-1 recruited cellular fusion regulatory proteins CD98hc and β1 integrin to the nuclear membrane for viral de-envelopment fusion. This is the first report of cellular proteins required for efficient de-envelopment of macromolecular complexes during their nuclear egress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism
  • Cell Nucleus / virology
  • Fusion Regulatory Protein 1, Heavy Chain / genetics
  • Fusion Regulatory Protein 1, Heavy Chain / metabolism*
  • Herpes Simplex / genetics
  • Herpes Simplex / metabolism*
  • Herpes Simplex / virology
  • Herpesvirus 1, Human / genetics
  • Herpesvirus 1, Human / physiology*
  • Humans
  • Integrin beta1 / genetics
  • Integrin beta1 / metabolism*
  • Nuclear Envelope / metabolism
  • Nuclear Envelope / virology*
  • Protein Binding
  • Viral Proteins / genetics
  • Viral Proteins / metabolism
  • Virus Uncoating*

Substances

  • Fusion Regulatory Protein 1, Heavy Chain
  • Integrin beta1
  • Viral Proteins