Cascade of events governing cell-cell fusion induced by herpes simplex virus glycoproteins gD, gH/gL, and gB.
Herpesviruses minimally require the envelope proteins gB and gH/gL for virus entry and cell-cell fusion; herpes simplex virus (HSV) additionally requires the receptor-binding protein gD. Although gB is a class III fusion protein, gH/gL does not resemble any documented viral fusion protein at a structural level. Based on those data, we proposed that gH/gL does not function as a cofusogen with gB but instead regulates the fusogenic activity of gB. Here, we present data to support that hypothesis. First, receptor-positive B78H1-C10 cells expressing gH/gL fused with receptor-negative B78H1 cells expressing gB and gD (fusion in trans). Second, fusion occurred when gH/gL-expressing C10 cells preexposed to soluble gD were subsequently cocultured with gB-expressing B78 cells. In contrast, prior exposure of gB-expressing C10 cells to soluble gD did not promote subsequent fusion with gH/gL-expressing B78 cells. These data suggest that fusion involves activation of gH/gL by receptor-bound gD. Most importantly, soluble gH/gL triggered a low level of fusion of C10 cells expressing gD and gB; a much higher level was achieved when gB-expressing C10 cells were exposed to a combination of soluble gH/gL and gD. These data clearly show that gB acts as the HSV fusogen following activation by gD and gH/gL. We suggest the following steps leading to fusion: (i) conformational changes to gD upon receptor binding, (ii) alteration of gH/gL by receptor-activated gD, and (iii) upregulation of the fusogenic potential of gB following its interaction with activated gH/gL. The third step may be common to other herpesviruses.
Atanasiu
Doina
D
Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. doinaa2@biochem.dental.upenn.edu
Saw
Wan Ting
WT
Cohen
Gary H
GH
Eisenberg
Roselyn J
RJ
D000818:Animals; D002459:Cell Fusion; D002460:Cell Line; D005455:Fluorescent Antibody Technique; D015726:Giant Cells / Q000166:cytology; D008561:Membrane Fusion / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D010957:Plasmids / Q000235:genetics; D018139:Simplexvirus / Q000378:metabolism*; D014759:Viral Envelope Proteins / Q000378:metabolism*
D008562:Membrane Glycoproteins; D014759:Viral Envelope Proteins