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...
Enveloped viruses typically encode their own fusion machinery to enter cells. Herpesviruses are unusual, as they fuse with a number of cellular compartments throughout their life cycles. As uncontrolled fusion of the host membranes should be avoided in these events, tight regulation of the viral fusion machinery is critical. While studying herpes simplex virus 1 (HSV-1) glycoprotein gM, we identified the cellular protein E-Syt1 (extended synaptotagmin 1) as an interaction partner. The interaction took place in both infected and transfected cells, suggesting other viral proteins were not required for the interaction. Most interestingly, E-Syt1 is a member of the synaptotagmin family of membrane fusion regulators. However, the protein is known to promote the tethering of the endoplasmic reticulum (ER) to the plasma membrane. We now show that E-Syt1, along with the related E-Syt3, negatively modulates viral release into the extracellular milieu, cell-to-cell viral spread, and viral entry, all processes that implicate membrane fusion events. Similarly, these E-Syt proteins impacted the formation of virus-induced syncytia. Altogether, these findings hint at the modulation of the viral fusion machinery by the E-Syt family of proteins. Viruses typically encode their own fusion apparatus to enable them to enter cells. For many viruses, this means a single fusogenic protein. However, herpesviruses are large entities that express several accessory viral proteins to regulate their fusogenic activity. The present study hints at the additional participation of cellular proteins in this process, suggesting the host can also modulate viral fusion to some extent. Hence E-Syt proteins 1 and 3 seem to negatively modulate the different viral fusion events that take place during the HSV-1 life cycle. This could represent yet another innate immunity response to the virus.
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