Involvement of gD/HVEM interaction in NF-kB-dependent inhibition of apoptosis by HSV-1 gD.
In the present paper, we aimed to verify whether the interaction of the glycoprotein D (gD) of herpes simplex 1 (HSV-1) with the HSV-1 receptor HVEM is involved in NF-kappaB-dependent protection against apoptosis by gD. To this purpose, first we utilized MAbs that interfere with gD/HVEM interaction and U937 cells that naturally express human HVEM on their surface. Pre-incubation with these MAbs, but not with a control antibody, partially reverted the protection of infectious HSV-1 towards anti-Fas induced apoptosis in U937 cells. Similarly, pre-incubation of UV-inactivated HSV-1 (UV-HSV-1) or recombinant gD with the same MAbs, significantly reduced the inhibition of Fas-mediated apoptosis by UV-HSV-1 or gD, respectively, in U937 cells. Moreover, coculture with stable transfectants expressing at surface level wild type gD protected U937 cells against Fas-induced apoptosis, while coculture with transfectants expressing a mutated form of gD, incapable to bind HVEM, did not protect. Finally, UV-HSV-1 protected against staurosporine-induced apoptosis in U937 cells as well as in the CHO transfectants expressing human HVEM on their surface, but not in the control CHO transfectants, which did not express HVEM. These results suggest that signaling triggered by binding of gD to HVEM could represent an additional mechanism of evasion from premature apoptotic death exerted by HSV-1-gD in HVEM-expressing cells, disclosing new opportunities of cell death manipulation by using gD preparations.
Sciortino
Maria Teresa
MT
Department of Life Sciences, Section of Microbiological, Genetic and Molecular Sciences, University of Messina, Salita Sperone 31, 98166 Messina, Italy.
Medici
Maria Antonietta
MA
Marino-Merlo
Francesca
F
Zaccaria
Daniela
D
Giuffrè-Cuculletto
Maria
M
Venuti
Assunta
A
Grelli
Sandro
S
Bramanti
Placido
P
Mastino
Antonio
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D002522:Chlorocebus aethiops; D018920:Coculture Techniques; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D016328:NF-kappa B / Q000502:physiology*; D009500:Neutralization Tests; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology; D020298:U937 Cells; D014709:Vero Cells; D014759:Viral Envelope Proteins / Q000276:immunology / Q000502:physiology*
D000911:Antibodies, Monoclonal; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D053240:Receptors, Tumor Necrosis Factor, Member 14; C506028:TNFRSF14 protein, human; D014759:Viral Envelope Proteins; C039447:glycoprotein D, Human herpesvirus 1; D053148:Caspase 3; D019311:Staurosporine