Participation of 3‐O‐sulfated heparan sulfates in the protection of macrophages by herpes simplex virus‐1 glycoprotein D and cyclophilin B against apoptosis

• Published in: FEBS open bio Vol. 7; no. 2; pp. 133 - 148
• Main Authors: Delos, Maxime, Hellec, Charles, Foulquier, François, Carpentier, Mathieu, Allain, Fabrice, Denys, Agnès
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.02.2017; John Wiley and Sons Inc
• Subjects: Acids; Apoptosis; Binding sites; Cell activation; cyclophilin; Experiments; Glycoprotein D; Glycoproteins; heparan sulfates; Herpes simplex; Herpes viruses; HSV‐1 glycoprotein D; Immunoglobulins; Kinases; Ligands; Macrophages; Nectin; Software; Sulfotransferase; France; Germany; HSV‐1 glycoprotein D; apoptosis; macrophages; cyclophilin; heparan sulfates
• ISSN: 2211-5463; 2211-5463
• DOI: 10.1002/2211-5463.12145

Heparan sulfates (HS) are involved in numerous biological processes, which rely on their ability to interact with a large panel of proteins. Although the reaction of 3‐O‐sulfation can be catalysed by the largest family of HS sulfotransferases, very few mechanisms have been associated with this modification and to date, only glycoprotein D (gD) of herpes simplex virus‐1 (HSV‐1 gD) and cyclophilin B (CyPB) have been well‐described as ligands for 3‐O‐sulfated HS. Here, we hypothesized that both ligands could induce the same responses via a mechanism dependent on 3‐O‐sulfated HS. First, we checked that HSV‐1 gD was as efficient as CyPB to induce the activation of the same signalling events in primary macrophages. We then demonstrated that both ligands efficiently reduced staurosporin‐induced apoptosis and modulated the expression of apoptotic genes. In addition to 3‐O‐sulfated HS, HSV‐1 gD was reported to interact with other receptors, including herpes virus entry mediator (HVEM), nectin‐1 and ‐2. Thus, we decided to identify the contribution of each binding site in the responses triggered by HSV‐1 gD and CyPB. We found that knock‐down of 3‐O‐sulfotransferase 2, which is the main 3‐O‐sulfated HS‐generating enzyme in macrophages, strongly reduced the responses induced by both ligands. Moreover, silencing the expression of HVEM rendered macrophages unresponsive to either HSV‐1 gD and CyPB, thus indicating that both proteins induced the same responses by interacting with a complex formed by 3‐O‐sulfated HS and HVEM. Collectively, our results suggest that HSV‐1 might hijack the binding sites for CyPB in order to protect macrophages against apoptosis for efficient infection. Herpes simplex virus‐1 glycoprotein D (HSV‐1 gD) and cyclophilin B (CyPB) protect macrophages against apoptosis by interacting with herpes virus entry mediator and 3‐O‐sulfated heparan sulfates. HSV‐1 gD and CyPB induce the activation of NF‐κB, Akt and extracellular signal‐regulated kinases 1/2 pathways and regulate the expression of apoptotic genes. Collectively, these results suggest that HSV‐1 hijacks the binding sites of CyPB to promote survival of macrophages.