Genetic Analysis of the Herpes Simplex Virus Type 1 UL20 Protein Domains Involved in Cytoplasmic Virion Envelopment and Virus-Induced Cell Fusion

Melancon, Jeffrey M.; Foster, Timothy P.; Kousoulas, Konstantin G.

doi:10.1128/jvi.78.14.7329-7343.2004

Cited by 49 publications

(101 citation statements)

References 43 publications

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“…In apparent contrast, gM was recently reported to stimulate viral entry, i.e., the fusion of the viral envelope with the cell surface in the context of strong syncytial strains (22). Interestingly, both cases involve "forced situations" where the fine controls of virally induced fusion were deregulated, as has been the case with the various syncytial strains studied in the past, all of which involve mutations (41)(42)(43)(44)(45)(46)(47)(48)(49). De- with HSV-1⌬gM2 virus at an MOI of 5, and the cells were harvested at 16 hpi and lysed.…”

Section: Discussionmentioning

confidence: 90%

Herpes Simplex Virus 1 gN Partners with gM To Modulate the Viral Fusion Machinery

Kasmi

Lippé

2015

J Virol

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Herpes simplex virus 1 (HSV-1) capsids are assembled in the nucleus, where they incorporate the viral genome. They then transit through the two nuclear membranes and are wrapped by a host-derived envelope. In the process, several HSV-1 proteins are targeted to the nuclear membranes, but their roles in viral nuclear egress are unclear. Among them, glycoprotein M (gM), a known modulator of virus-induced membrane fusion, is distributed on both the inner and outer nuclear membranes at the early stages of the infection, when no other viral glycoproteins are yet present there. Later on, it is found on perinuclear virions and ultimately redirected to the trans-Golgi network (TGN), where it cycles with the cell surface. In contrast, transfected gM is found only at the TGN and cell surface, hinting at an interaction with other viral proteins. Interestingly, many herpesvirus gM analogs interact with their gN counterparts, which typically alters their intracellular localization. To better understand how HSV-1 gM localization is regulated, we evaluated its ability to bind gN and discovered it does so in both transfected and infected cells, an interaction strongly weakened by the deletion of the gM amino terminus. Functionally, while gN had no impact on gM localization, gM redirected gN from the endoplasmic reticulum (ER) to the TGN. Most interestingly, gN overexpression stimulated the formation of syncytia in the context of an infection by a nonsyncytial strain, indicating that gM and gN not only physically but also functionally interact and that gN modulates gM's activity on membrane fusion. H erpesviridae are among the most complex human viruses from the point of view of their large genomes and viral particle composition. Among them, herpes simplex virus 1 (HSV-1), the prototype of human alphaherpesviruses, incorporates its 152-kb genome into an icosahedral capsid surrounded by a multiprotein tegument layer and a cell-derived lipid layer containing over a dozen viral proteins (1, 2). Of the latter, those mediating viral entry, namely, gB, gD, and the gH/gL complex, are essential for the propagation of the virus (3). In contrast, the viral glycoprotein M (gM) is conserved throughout the family and typically critical for beta-and gammaherpesviruses but is not essential for most alphaherpesviruses, including HSV-1 (4-16). Consequently, when gM is depleted from HSV-1 or the related alphaherpesvirus pseudorabies virus, viral yields are minimally reduced by 3-to 50-fold. However, its impact is substantially increased when U L 11 and gE/gI are codepleted in combination with gM, likely due to overlapping functions between these viral proteins (5,(17)(18)(19). IMPORTANCE HSV-1 gM is an important modulator of virally induced cell-cell fusion and viral entry, a process that is likely finely modulatedDespite its nonessential status in tissue culture, gM of several alphaherpesviruses has been associated with a number of functions throughout the viral life cycle (7,10,(19)(20)(21)(22). The glycoprotein is thus known to downregu...

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Section: Discussionmentioning

confidence: 90%

Herpes Simplex Virus 1 gN Partners with gM To Modulate the Viral Fusion Machinery

Kasmi

Lippé

2015

J Virol

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confidence: 83%

“…Moreover, both transport of gK to cell surfaces and gK-mediated cell-to-cell fusion were abolished in UL20-null virus-infected cells (25). Taken together, these results suggest a functional interdependence between gK and UL20 for intracellular protein trafficking, virus egress, and virus-mediated cell-to-cell fusion (19,23,25,29,53).Recent observations that both UL20-null and gK-null virions accumulated within TGN-like cytoplasmic vesicles (24,25,39) prompted the detailed examination of the cellular localization and interdependent transport of gK and UL20p. In this report, we show that UL20p and gK are mutually dependent for post-endoplasmic reticulum (ER) transport and specifically colocalize to the TGN after endocytosis from cell surfaces.…”

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confidence: 99%

“…Although both proteins have multiple sites where posttranslational modification can occur, only gK is posttranslationally modified by N-linked carbohydrate addition (16,34,60). Viruses that specify deletions in either of these proteins are unable to translocate from the cytoplasm to extracellular spaces and accumulate enveloped virions within TGN-like cytoplasmic vesicles (1,24,25,29,35,39,53). Moreover, both transport of gK to cell surfaces and gK-mediated cell-to-cell fusion were abolished in UL20-null virus-infected cells (25).…”

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confidence: 99%

“…Mutations that cause extensive virus-induced cell-to-cell fusion have been mapped to at least four regions of the viral genome: the UL20 gene (1,50,53), the UL24 gene (38,64), the UL27 gene encoding glycoprotein B (gB) (9,57), and the UL53 gene coding for gK (3,16,34,58,59,63). Of these four membraneassociated proteins, UL20p and gK are essential for the intracellular transport of virions to extracellular spaces (1,25,29,35,39,55).…”

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Herpes Simplex Virus Type 1 Glycoprotein K and the UL20 Protein Are Interdependent for Intracellular Trafficking andtrans-Golgi Network Localization

Foster

Melancon

Olivier

et al. 2004

J Virol

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Final envelopment of the cytoplasmic herpes simplex virus type 1 (HSV-1) nucleocapsid is thought to occur by budding into trans-Golgi network (TGN)-derived membranes. The highly membrane-associated proteins UL20p and glycoprotein K (gK) are required for cytoplasmic envelopment at the TGN and virion transport from the TGN to extracellular spaces. Furthermore, the UL20 protein is required for intracellular transport and cell surface expression of gK. Independently expressed gK or UL20p via transient expression in Vero cells failed to be transported from the endoplasmic reticulum (ER). Similarly, infection of Vero cells with either gK-null or UL20-null viruses resulted in ER entrapment of UL20p or gK, respectively. In HSV-1 wild-type virus infections and to a lesser extent in transient gK and UL20p coexpression experiments, both gK and UL20p localized to the Golgi apparatus. In wild-type, but not UL20-null, viral infections, gK was readily detected on cell surfaces. In contrast, transiently coexpressed gK and UL20p predominantly localized to the TGN and were not readily detected on cell surfaces. However, TGN-localized gK and UL20p originated from endocytosed gK and UL20p expressed at cell surfaces. Retention of UL20p to the ER through the addition of an ER retention motif forced total ER retention of gK, indicating that transport of gK is absolutely dependent on UL20p transport. In all experiments, gK and UL20p colocalized at intracellular sites, including the ER, Golgi, and TGN. These results are consistent with the hypothesis that gK and UL20p directly interact and that this interaction facilitates their TGN localization, an important prerequisite for cytoplasmic virion envelopment and egress.It is widely accepted that herpesvirus egress entails a twostage envelopment process. Initially, capsids assemble within the nuclei and virions acquire an initial envelope by budding into the perinuclear spaces. Subsequently, these enveloped virions lose their envelope by fusion with the outer nuclear lamellae. Within the cytoplasm, tegument proteins associate with the viral nucleocapsid and final envelopment occurs by budding of cytoplasmic capsids into specific trans-Golgi network (TGN)-associated membranes. Mature virions subsequently traffic to cell surfaces, presumably following the cellular secretory pathway (31,54,65). Although several lines of evidence support this model of TGN assembly and egress (8,30,54,76), the specific viral and cellular mechanisms responsible for the targeted trafficking of viral envelope glycoproteins to intracellular sites of virion envelopment are only recently being elucidated.Herpes simplex viruses (HSVs) specify at least 11 virally encoded glycoproteins, as well as several nonglycosylated membrane-associated proteins, that are pivotal in membrane fusion processes during a productive viral infection. Mutations that cause extensive virus-induced cell-to-cell fusion have been mapped to at least four regions of the viral genome: the UL20 gene (1,50,53), the UL24 gene (38, 64), the UL27 gene ...

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Virus Assembly and Egress of HSV

Crump

2018

Advances in Experimental Medicine and Biology

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The assembly and egress of herpes simplex virus (HSV) is a complicated multistage process that involves several different cellular compartments and the activity of many viral and cellular proteins. The process begins in the nucleus, with capsid assembly followed by genome packaging into the preformed capsids. The DNA-filled capsids (nucleocapsids) then exit the nucleus by a process of envelopment at the inner nuclear membrane followed by fusion with the outer nuclear membrane. In the cytoplasm nucleocapsids associate with tegument proteins, which form a complicated protein network that links the nucleocapsid to the cytoplasmic domains of viral envelope proteins. Nucleocapsids and associated tegument then undergo secondary envelopment at intracellular membranes originating from late secretory pathway and endosomal compartments. This leads to assembled virions in the lumen of large cytoplasmic vesicles, which are then transported to the cell periphery to fuse with the plasma membrane and release virus particles from the cell. The details of this multifaceted process are described in this chapter.

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Genetic Analysis of the Herpes Simplex Virus Type 1 UL20 Protein Domains Involved in Cytoplasmic Virion Envelopment and Virus-Induced Cell Fusion

Cited by 49 publications

References 43 publications

Herpes Simplex Virus 1 gN Partners with gM To Modulate the Viral Fusion Machinery

Herpes Simplex Virus 1 gN Partners with gM To Modulate the Viral Fusion Machinery

Herpes Simplex Virus Type 1 Glycoprotein K and the UL20 Protein Are Interdependent for Intracellular Trafficking andtrans-Golgi Network Localization

Virus Assembly and Egress of HSV

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