Members of 3-O-Sulfotransferases (3-OST) Family: A Valuable Tool from Zebrafish to Humans for Understanding Herpes Simplex Virus Entry

Abstract

The journey of many viruses to infect cells begins when the virus first binds to cell surface heparan sulfate (HS). The initial step of cell attachment or binding during herpes simplex virus type-1 (HSV-1) entry is mediated by envelope glycoprotein B (gB) and C (gC). The binding is followed by fusion between virus envelope and cell membrane during which HSV-1 glycoprotein D (gD) interacts with a modified form of HS know as 3-O-sulfated heparan sulfate (3-OS HS). The rare modification of 3-O-sulfation on HS chain is governed by enzymes known as 3-O-sulfotransferase (3-OST). Currently, there are seven isoforms of human 3-OSTs that have been identified, and with the exception of 3-OST-1, all other 3-OST isoforms allow HSV-1 entry and spread. Recently, the product of the zebrafish (ZF)-encoded 3-OST-3 was also recognized as a gD receptor, which mediates HSV-1 entry and cell-cell fusion similar to human 3-OST-3. Interestingly, the ZF system expresses multiple isoforms of 3-OST which could be very useful for studying the involvement of HS and 3-OS HS in virus tropism and virus-induced inflammation. In addition, therapeutic targeting of 3-OST generated HS is likely to bring about novel interventions against HSV-1. In this review we have taken a closer look at the potential of both human and ZF encoded 3-OSTs as valuable tools in HSV entry and inflammation studies.

Keywords: HSV; heparan sulfate; modified form of heparan sulfate.; viral entry.

Fig. (1)

Back bone of cell surface heparan sulfate (HS): Shown is the representative of disaccharide unit consisting of a glucuronic acid (GlcA) and N-acetylated glucosamine (GlcNAc) residue.

Fig. (2)

Panels A-B showing types of heparan sulfate (HS) on cell surface: (Panel A) plain vanilla-type of unmodified HS and (Panel B) modified form of HS. The modified form of HS is represented by 3-O-sulfation by 3-OST-2, 3, 4, 5 and 6 isoforms. (Panel C): Multiple roles of HS during HSV-1 pathogenesis. This includes initial binding of HSV-1 glycoprotein B (gB) and C (gC) to plain-vanilla-type HS (upper panel), viral cell fusion in which modified from of HS, 3-OS HS, interacts with HSV-1 gD to mediate this process (middle panel) and finally both HS and modified HS are involved in viral spread from cell-to-cell in which four HSV-1 glycoprotein’s: gB, gD, gH and gL are involved (lower panel).