The XPO6 Exportin Mediates Herpes Simplex Virus 1 gM Nuclear Release Late in Infection

Abstract

The mechanisms that enable integral proteins to be targeted to the inner nuclear membrane are poorly understood. Herpes simplex virus 1 (HSV-1) glycoprotein M (gM) is an interesting candidate, as it is dynamically relocalized from nuclear envelopes to the trans -Golgi network (TGN) in a virus- and time-dependent fashion. However, it was, until now, unclear how gM was directed to the nucleus or evaded that compartment later on. Through a proteomic study relying on a proximity-ligation assay, we identified several novel gM interacting partners, many of which are involved in vesicular transport. Analysis of select proteins revealed that XPO6 is required for gM to leave the nuclear membranes late in the infection. This was unexpected, as XPO6 is an exportin specifically associated with actin/profilin nuclear export. This raises some very interesting questions about the interaction of HSV-1 with the exportin machinery and the cargo specificity of XPO6.