title: A viral regulator of glycoprotein complexes contributes to human cytomegalovirus cell tropism.
abstract: Viral glycoproteins mediate entry of enveloped viruses into cells and thus play crucial roles in infection. In herpesviruses, a complex of two viral glycoproteins, gH and gL (gH/gL), regulates membrane fusion events and influences virion cell tropism. Human cytomegalovirus (HCMV) gH/gL can be incorporated into two different protein complexes: a glycoprotein O (gO)-containing complex known as gH/gL/gO, and a complex containing UL128, UL130, and UL131 known as gH/gL/UL128-131. Variability in the relative abundance of the complexes in the virion envelope correlates with differences in cell tropism exhibited between strains of HCMV. Nonetheless, the mechanisms underlying such variability have remained unclear. We have identified a viral protein encoded by the UL148 ORF (UL148) that influences the ratio of gH/gL/gO to gH/gL/UL128-131 and the cell tropism of HCMV virions. A mutant disrupted for UL148 showed defects in gH/gL/gO maturation and enhanced infectivity for epithelial cells. Accordingly, reintroduction of UL148 into an HCMV strain that lacked the gene resulted in decreased levels of gH/gL/UL128-131 on virions and, correspondingly, decreased infectivity for epithelial cells. UL148 localized to the endoplasmic reticulum, but not to the cytoplasmic sites of virion envelopment. Coimmunoprecipitation results indicated that gH, gL, UL130, and UL131 associate with UL148, but that gO and UL128 do not. Taken together, the findings suggest that UL148 modulates HCMV tropism by regulating the composition of alternative gH/gL complexes.
authors.affiliation: Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, LA 71103; leoleegangli@gmail.com jkamil@lsuhsc.edu.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, LA 71103;
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Nguyen
authors.affiliation: Division of Biological Sciences, Cellular, Molecular and Microbial Biology Program, and Center for Biomolecular Structure and Dynamics, University of Montana, Missoula, MT 59812; and.
authors.forename: Brent J
authors.initials: BJ
authors.lastname: Ryckman
authors.affiliation: Departments of Microbiology and Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35233.
authors.forename: William J
authors.initials: WJ
authors.lastname: Britt
authors.affiliation: Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, LA 71103; leoleegangli@gmail.com jkamil@lsuhsc.edu.
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Kamil
mesh_terms: D002467:Cell Nucleus / Q000378:metabolism; D022202:Chromosomes, Artificial, Bacterial; D003587:Cytomegalovirus / Q000378:metabolism* / Q000502:physiology; D003593:Cytoplasm / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000821:virology; D005347:Fibroblasts / Q000378:metabolism / Q000821:virology; D006023:Glycoproteins / Q000378:metabolism*; D006026:Glycoside Hydrolases / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D018613:Microscopy, Confocal; D009154:Mutation; D014759:Viral Envelope Proteins / Q000235:genetics; D014760:Viral Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D056189:Viral Tropism; D014771:Virion / Q000378:metabolism
chemical_list: D006023:Glycoproteins; D008562:Membrane Glycoproteins; C000598883:UL148 protein, human cytomegalovirus; D014759:Viral Envelope Proteins; D014760:Viral Fusion Proteins; D006026:Glycoside Hydrolases
keywords: UL148; endoplasmic reticulum; herpesvirus; infectious disease; viral glycoproteins
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