Seeking Closure: How Do Herpesviruses Recruit the Cellular ESCRT Apparatus?

Abstract

The Herpesviridae are structurally complex DNA viruses whose capsids undergo primary envelopment at the inner nuclear membrane and secondary envelopment at organelles in the cytoplasm. In both locations, there is evidence that envelope formation and scission involve the participation of multiple viral proteins and also the cellular ESCRT apparatus. It nevertheless appears that the best-understood viral strategies for ESCRT recruitment, those adopted by the retroviruses and many other families of enveloped RNA viruses, are not utilized by the Herpesviridae, at least during envelopment in the cytoplasm. Thus, although a large number of herpesvirus proteins have been assigned roles in envelopment, there is a dearth of candidates for the acquisition of the ESCRT complex and the control of envelope scission. This review summarizes our current understanding of ESCRT association by enveloped viruses, examines what is known of herpesvirus ESCRT utilization in the nucleus and cytoplasm, and identifies candidate cellular and viral proteins that could link enveloping herpesviruses to cellular ESCRT components.

Keywords: ESCRT; Herpesviridae; envelopment.

FIG 1

The ESCRT apparatus and its utilization by enveloped viruses. The ESCRT-0 complex (STAM/HRS) is shown in brown, ESCRT-I (TSG101/MVB12/VPS37/VPS28) in red, and ESCRT-II (EAP30/EAP45/EAP20₂) in yellow. The ESCRT-III filament is shown as a polymer of CHMP2/3/4 subunits (green) capped by nucleating CHMP6 subunits (cyan). ESCRT-II complex EAP20 subunits nucleate filament assembly through the recruitment of CHMP6. ALIX is represented as a blue cylinder making contacts with ESCRT-I and extending its Bro1 domain (gray) to trigger CHMP4 polymerization. Nedd4 family members are shown in purple. Individual viruses or virus families in which one or more members have been reported to utilize Nedd4, ALIX, or an ESCRT complex during envelopment are indicated by boxes of the corresponding color.

FIG 2

HSV-1 and EBV NECs and their interactions with ESCRT components. The soluble and membrane-anchored subunits of the herpesvirus NEC are shown in purple and red, respectively, with the lipid bilayer of the INM shown in gray at the bottom. ESCRT components or other relevant molecules that interact with the HSV-1 NEC (UL31p/UL34p) or the EBV NEC (BFLF2/BFRF1) are shown at the left and right of the NEC, respectively. Proteins are represented as touching an NEC subunit in cases where published data imply direct physical contact. Proteins present in a complex with the NEC subunit are connected by a solid line. Dashed lines indicate that the NEC complex influences the distribution of the protein but that no direct or indirect contact has been demonstrated. Purple spheres on EBV BFRF1 (Ub) represent polyubiquitin chains (Poly-Ub) covalently attached to lysine residues.

FIG 3

Generalized structure of an alphaherpesvirus cytoplasmic envelopment intermediate. The capsid (pink hexagon) is surrounded by an inner tegument (gray ovals) composed of UL36p/UL37p. This is the foundation for the attachment of the outer tegument subunits (shown in dark blue, cyan, orange, and dark gray), some of which interact with membrane-embedded envelope glycoproteins. There are multiple membrane proteins in the mature alphaherpesvirus envelope, but for clarity, only gB (purple), the gH/gL complex (yellow), and gD (pink) are shown (gD is absent from the alphaherpesvirus VZV). The ESCRT-III filament is assembled from CHMP subunits (green spheres) at the open bud neck. ESCRT-III will constrict to draw the membrane together, sealing the envelope and pinching the enveloped virus into the organellar lumen (light blue space). Constriction and ESCRT-III disassembly are catalyzed by the ATPase Vps4 (not shown).