Abstract
Herpesvirus capsids are assembled in the nucleus and undergo a two-step process to cross the nuclear envelope. Capsids bud into the inner nuclear membrane (INM) aided by the nuclear egress complex (NEC) proteins UL31/34. At that stage of egress, enveloped virions are found for a short time in the perinuclear space. In the second step of nuclear egress, perinuclear enveloped virions (PEVs) fuse with the outer nuclear membrane (ONM) delivering capsids into the cytoplasm. Once in the cytoplasm, capsids undergo re-envelopment in the Golgi/trans-Golgi apparatus producing mature virions. This second step of nuclear egress is known as de-envelopment and is the focus of this review. Compared with herpesvirus envelopment at the INM, much less is known about de-envelopment. We propose a model in which de-envelopment involves two phases: (i) fusion of the PEV membrane with the ONM and (ii) expansion of the fusion pore leading to release of the viral capsid into the cytoplasm. The first phase of de-envelopment, membrane fusion, involves four herpes simplex virus (HSV) proteins: gB, gH/gL, gK and UL20. gB is the viral fusion protein and appears to act to perturb membranes and promote fusion. gH/gL may also have similar properties and appears to be able to act in de-envelopment without gB. gK and UL20 negatively regulate these fusion proteins. In the second phase of de-envelopment (pore expansion and capsid release), an alpha-herpesvirus protein kinase, US3, acts to phosphorylate NEC proteins, which normally produce membrane curvature during envelopment. Phosphorylation of NEC proteins reverses tight membrane curvature, causing expansion of the membrane fusion pore and promoting release of capsids into the cytoplasm.
Highlights
Herpesviruses construct their nucleocapsids and fill them with DNA in the nucleus.These large virus particles face the difficult challenge of crossing the nuclear envelope (NE), a structure that is not designed to allow large objects to pass
There was controversy, with one camp suggesting that herpes simplex virus (HSV) acquires an envelope by budding into the inner nuclear membrane (INM) and that these enveloped particles acquire a second membrane at the outer nuclear membrane (ONM) [1]
Given the hypothesis that HSV gK negatively regulates the capacity of gB to fuse membranes, the observations of marked accumulation of perinuclear virions (PEVs) with overexpression of gK supports a model in which gK reduces gB-mediated membrane fusion between the virus and the ONM
Summary
Herpesviruses construct their nucleocapsids and fill them with DNA in the nucleus. These large virus particles face the difficult challenge of crossing the nuclear envelope (NE), a structure that is not designed to allow large objects to pass. All four fusion loop mutants expressed in viruses lacking gH accumulated PEVs, and there were fewer enveloped virions on cell surfaces [15] These results support the hypothesis that gB functions directly in membrane fusion to promote nuclear egress, rather than in other processes such as binding receptors or other viral proteins. Given the hypothesis that HSV gK negatively regulates the capacity of gB to fuse membranes, the observations of marked accumulation of PEVs with overexpression of gK supports a model in which gK reduces gB-mediated membrane fusion between the virus and the ONM It is not clear whether overexpression of gK impairs gH/gL in the de-envelopment process. Summary of the Roles of HSV Membrane Proteins gB, gH/gL, gK and UL20 in Nuclear Egress Mutants lacking both gB and gH accumulated enveloped particles in the perinuclear space or herniations. There is good evidence that there are other mechanisms by which HSV and other herpesviruses cross the ONM (see Section 3 below)
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