Human Herpesvirus 6 and Measles Virus Employ Distinct CD46 Domains for Receptor Function.
We employed a quantitative cell fusion assay to identify structural domains of CD46 required for its function as a receptor for human herpesvirus 6 (HHV-6). We examined the activities of recombinant variants of CD46, including different isoforms as well as engineered truncations and molecular chimeras with decay-accelerating factor, a related protein in the family of regulators of complement activation (RCA). We observed strong receptor activity for all four CD46 isoforms, which differ in the membrane-proximal extracellular and cytoplasmic domains, indicating that the critical determinants for HHV-6 receptor activity reside outside the C-terminal portion of CD46. Analysis of the short consensus repeat (SCR) regions that comprise most of the extracellular portion of CD46 indicated a strong dependence on SCRs 2 and 3 and no requirement for SCRs 1 or 4. Fusion-inhibition studies with SCR-specific monoclonal antibodies supported the essential role of SCRs 2 and 3 in HHV-6 receptor activity. These findings contrast markedly with fusion mediated by measles virus glycoproteins for which we observed a strict dependence on SCRs 1 and 2, consistent with previous reports. These results expand the emerging notion that CD46 and other members of the RCA family are co-opted in distinct manners by different infectious pathogens.
Greenstone
Heather L
HL
NIAID, National Institutes of Health, Bethesda, Maryland 20892, USA.
Santoro
Fabio
F
Lusso
Paolo
P
Berger
Edward A
EA
D016475:3T3 Cells; D000818:Animals; D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000096:biosynthesis* / Q000737:chemistry; D002478:Cells, Cultured; D002874:Chromosome Mapping; D003167:Complement Activation; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006367:HeLa Cells; D015654:Herpesvirus 6, Human / Q000378:metabolism*; D006801:Humans; D007763:Lac Operon; D008459:Measles virus / Q000235:genetics*; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000737:chemistry; D051379:Mice; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D011991:Receptors, Virus / Q000737:chemistry* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C497857:CD46 protein, human; C497859:Mcp protein, mouse; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D020033:Protein Isoforms; D011991:Receptors, Virus