Host and Viral Factors Involved in Nuclear Egress of Herpes Simplex Virus 1

Abstract

Herpes simplex virus 1 (HSV-1) replicates its genome and packages it into capsids within the nucleus. HSV-1 has evolved a complex mechanism of nuclear egress whereby nascent capsids bud on the inner nuclear membrane to form perinuclear virions that subsequently fuse with the outer nuclear membrane, releasing capsids into the cytosol. The viral-encoded nuclear egress complex (NEC) plays a crucial role in this vesicle-mediated nucleocytoplasmic transport. Nevertheless, similar system mediates the movement of other cellular macromolecular complexes in normal cells. Therefore, HSV-1 may utilize viral proteins to hijack the cellular machinery in order to facilitate capsid transport. However, little is known about the molecular mechanisms underlying this phenomenon. This review summarizes our current understanding of the cellular and viral factors involved in the nuclear egress of HSV-1 capsids.

Keywords: de-envelopment; herpesviruses; nuclear egress; primary envelopment.

Figure 1

Overview of nuclear egress. (A) Illustration of a ‘normal’ nuclear envelope. INM, inner nuclear membrane; ONM, outer nuclear membrane; NPC, nuclear pore complex; ER, endoplasmic reticulum. (B) Illustration of vesicle-mediated nucleocytoplasmic transport. A cargo (e.g., viral capsid) in the nucleus buds through the INM to form a vesicle in the perinuclear space that then fuses with the ONM to release the complex into the cytoplasm (de-envelopment).

Figure 2

Multiple proteins are involved in primary envelopment of HSV-1 capsids. NEC and kinases (e.g., PKCs and Us3) induce lamina dissociation to allow capsid recruitment to the INM. ICP34.5 and p32 contribute to the recruitment of PKCs. The NEC is responsible for capsid recruitment and mediates budding by assembling into a hexagonal lattice. CVSC decorates vertices of DNA-filled nucleocapsid and promotes nuclear egress through interaction with the NEC. Viral proteins (e.g., UL47 and ICP22) and cellular protein VAPB regulate primary envelopment through as-yet unidentified mechanisms. The NEC recruits ESCRT-III via ALIX to pinch off primary virions from the INM.

Figure 3

Multiple proteins are involved in the de-envelopment step. Some viral proteins, such as gB/gH and Us3 may be involved in the de-envelopment step, but their roles are unclear. Us3 may induce disassembly of the NEC lattice. Torsin and p32 promote de-envelopment through unidentified mechanisms. Viral protein UL47 interacts with cellular protein p32. The CD98hc/β1 integrin complex may influence fusion activity of the primary virions.

Figure 4

Proposed models of vesicle-mediated cytoplasmic transport in various situations. (A) A large RNP complex exits from the nucleus through vesicle-mediated nucleocytoplasmic transport system in Drosophila cells. (B) In ‘normal’ mammalian cells, torsins and ESCRT-III might contribute to eliminate excess INM and/or INM proteins. This process might be similar to the vesicle-mediated nucleocytoplasmic transport of HSV-1 nucleocapsids. (C) In torsin-deficient cells, herniations and vesicles containing NPC proteins within the perinuclear space are produced. (D) In ESCRT-III-deficient cells, INM proliferation is induced. (E) In cells from HGPS patients, progerin (mutant lamin A) accumulates in the nucleus, resulting in nuclear envelope deformation and defects including vesicles in the perinuclear space. ESCRT-III represses membrane deformation in these cells.