Herpesvirus glycoprotein M (gM) is a multiple-spanning integral membrane protein found within the envelope of mature herpesviruses and is conserved throughout the Herpesviridae. gM is defined as a non-essential glycoprotein in alphaherpesviruses and has been proposed as playing a role in controlling final envelopment in a late secretory-pathway compartment such as the trans-Golgi network (TGN). Additionally, gM proteins have been shown to inhibit cell–cell fusion in transfection-based assays by an as yet unclear mechanism. Here, the effect of pseudorabies virus (PRV) gM and the herpes simplex virus type 1 (HSV-1) gM/UL49A complex on the fusion events caused by the HSV-1 glycoproteins gB, gD, gH and gL was investigated. Fusion of cells expressing HSV-1 gB, gD, gH and gL was efficiently inhibited by both PRV gM and HSV-1 gM/UL49A. Furthermore, expression of PRV gM or HSV-1 gM/UL49A, which are themselves localized to the TGN, caused both gD and gH/L to be relocalized from the plasma membrane to a juxtanuclear compartment, suggesting that fusion inhibition is caused by the removal of ‘fusion’ proteins from the cell surface. The ability of gM to cause the relocalization of plasma membrane proteins was not restricted to HSV-1 glycoproteins, as other viral and non-viral proteins were also affected. These data suggest that herpesvirus gM (gM/N) can alter the membrane trafficking itineraries of a broad range of proteins and this may have multiple functions.
AdamsR.,
CunninghamC.,
DavisonM. D.,
MacLeanC. A.,
DavisonA. J.1998; Characterization of the protein encoded by gene UL49A of herpes simplex virus type 1. J Gen Virol 79:813–823
AlconadaA.,
BauerU.,
SodeikB.,
HoflackB.1999; Intracellular traffic of herpes simplex virus glycoprotein gE: characterization of the sorting signals required for its trans -Golgi network localization. J Virol 73:377–387
BainesJ. D.,
RoizmanB.1991; The open reading frames UL3, UL4, UL10, and UL16 are dispensable for the replication of herpes simplex virus 1 in cell culture. J Virol 65:938–944
BembridgeG. P.,
RodriguezN.,
Garcia-BeatoR.,
NicolsonC.,
MeleroJ. A.,
TaylorG.2000; Respiratory syncytial virus infection of gene gun vaccinated mice induces Th2-driven pulmonary eosinophilia even in the absence of sensitisation to the fusion (F) or attachment (G) protein. Vaccine 19:1038–1046[CrossRef]
BrackA. R.,
DijkstraJ. M.,
GranzowH.,
KluppB. G.,
MettenleiterT. C.1999; Inhibition of virion maturation by simultaneous deletion of glycoproteins E, I, and M of pseudorabies virus. J Virol 73:5364–5372
BuckmasterE. A.,
GompelsU.,
MinsonA.1984; Characterization and physical mapping of an HSV-1 glycoprotein of approximately 115×103 molecular weight. Virology 139:408–413[CrossRef]
CrumpC. M.,
XiangY.,
ThomasL.,
GuF.,
AustinC.,
ToozeS. A.,
ThomasG.2001; PACS-1 binding to adaptors is required for acidic cluster motif-mediated protein traffic. EMBO J 20:2191–2201[CrossRef]
CrumpC. M.,
HungC.-H.,
ThomasL.,
WanL.,
ThomasG.2003; Role of PACS-1 in trafficking of human cytomegalovirus glycoprotein B and virus production. J Virol 77:11105–11113[CrossRef]
DijkstraJ. M.,
VisserN.,
MettenleiterT. C.,
KluppB. G.1996; Identification and characterization of pseudorabies virus glycoprotein gM as a nonessential virion component. J Virol 70:5684–5688
FanZ.,
GranthamM. L.,
SmithM. S.,
AndersonE. S.,
CardelliJ. A.,
MuggeridgeM. I.2002; Truncation of herpes simplex virus type 2 glycoprotein B increases its cell surface expression and activity in cell–cell fusion, but these properties are unrelated. J Virol 76:9271–9283[CrossRef]
FarnsworthA.,
GoldsmithK.,
JohnsonD. C.2003; Herpes simplex virus glycoproteins gD and gE/gI serve essential but redundant functions during acquisition of the virion envelope in the cytoplasm. J Virol 77:8481–8494[CrossRef]
FavoreelH. W.,
NauwynckH. J.,
Van OostveldtP.,
PensaertM. B.2000; Role of anti-gB and -gD antibodies in antibody-induced endocytosis of viral and cellular cell surface glycoproteins expressed on pseudorabies virus-infected monocytes. Virology 267:151–158[CrossRef]
FordM. G.,
PearseB. M.,
HigginsM. K.,
VallisY.,
OwenD. J.,
GibsonA.,
HopkinsC. R.,
EvansP. R.,
McMahonH. T.2001; Simultaneous binding of PtdIns(4,5)P2 and clathrin by AP180 in the nucleation of clathrin lattices on membranes. Science 291:1051–1055[CrossRef]
FuchsW.,
MettenleiterT. C.1999; DNA sequence of the UL6 to UL20 genes of infectious laryngotracheitis virus and characterization of the UL10 gene product as a nonglycosylated and nonessential virion protein. J Gen Virol 80:2173–2182
HarmanA.,
BrowneH.,
MinsonT.2002; The transmembrane domain and cytoplasmic tail of herpes simplex virus type 1 glycoprotein H play a role in membrane fusion. J Virol 76:10708–10716[CrossRef]
HutchinsonL.,
BrowneH.,
WargentV.,
Davis-PoynterN.,
PrimoracS.,
GoldsmithK.,
MinsonA. C.,
JohnsonD. C.1992; A novel herpes simplex virus glycoprotein, gL, forms a complex with glycoprotein H (gH) and affects normal folding and surface expression of gH. J Virol 66:2240–2250
JonsA.,
GranzowH.,
KuchlingR.,
MettenleiterT. C.1996; The UL49·5 gene of pseudorabies virus codes for an O -glycosylated structural protein of the viral envelope. J Virol 70:1237–1241
KonigP.,
GiesowK.,
KeilG. M.2002; Glycoprotein M of bovine herpesvirus 1 (BHV-1) is nonessential for replication in cell culture and is involved in inhibition of bovine respiratory syncytial virus F protein induced syncytium formation in recombinant BHV-1 infected cells. Vet Microbiol 86:37–49[CrossRef]
KoppM.,
GranzowH.,
FuchsW.,
KluppB. G.,
MundtE.,
KargerA.,
MettenleiterT. C.2003; The pseudorabies virus UL11 protein is a virion component involved in secondary envelopment in the cytoplasm. J Virol 77:5339–5351[CrossRef]
KoyanoS.,
MarE. C.,
StameyF. R.,
InoueN.2003; Glycoproteins M and N of human herpesvirus 8 form a complex and inhibit cell fusion. J Gen Virol 84:1485–1491[CrossRef]
LakeC. M.,
Hutt-FletcherL. M.2000; Epstein–Barr virus that lacks glycoprotein gN is impaired in assembly and infection. J Virol 74:11162–11172[CrossRef]
LakeC. M.,
MolesworthS. J.,
Hutt-FletcherL. M.1998; The Epstein–Barr virus (EBV) gN homolog BLRF1 encodes a 15-kilodalton glycoprotein that cannot be authentically processed unless it is coexpressed with the EBV gM homolog BBRF3. J Virol 72:5559–5564
LiangX.,
ChowB.,
RaggoC.,
BabiukL. A.1996; Bovine herpesvirus 1 UL49·5 homolog gene encodes a novel viral envelope protein that forms a disulfide-linked complex with a second virion structural protein. J Virol 70:1448–1454
MachM.,
KropffB.,
Dal MonteP.,
BrittW.2000; Complex formation by human cytomegalovirus glycoproteins M (gpUL100) and N (gpUL73). J Virol 74:11881–11892[CrossRef]
MacLeanC. A.,
RobertsonL. M.,
JamiesonF. E.1993; Characterization of the UL10 gene product of herpes simplex virus type 1 and investigation of its role in vivo
. J Gen Virol 74:975–983[CrossRef]
McMillanT. N.,
JohnsonD. C.2001; Cytoplasmic domain of herpes simplex virus gE causes accumulation in the trans -Golgi network, a site of virus envelopment and sorting of virions to cell junctions. J Virol 75:1928–1940[CrossRef]
MettenleiterT. C.2003; Pathogenesis of neurotropic herpesviruses: role of viral glycoproteins in neuroinvasion and transneuronal spread. Virus Res 92:197–206[CrossRef]
MinsonA. C.,
HodgmanT. C.,
DigardP.,
HancockD. C.,
BellS. E.,
BuckmasterE. A.1986; An analysis of the biological properties of monoclonal antibodies against glycoprotein D of herpes simplex virus and identification of amino acid substitutions that confer resistance to neutralization. J Gen Virol 67:1001–1013[CrossRef]
MontgomeryR. I.,
WarnerM. S.,
LumB. J.,
SpearP. G.1996; Herpes simplex virus-1 entry into cells mediated by a novel member of the TNF/NGF receptor family. Cell 87:427–436[CrossRef]
OsterriederN.,
NeubauerA.,
BrandmullerC.,
BraunB.,
KaadenO. R.,
BainesJ. D.1996; The equine herpesvirus 1 glycoprotein gp21/22a, the herpes simplex virus type 1 gM homolog, is involved in virus penetration and cell-to-cell spread of virions. J Virol 70:4110–4115
OsterriederN.,
SeyboldtC.,
ElbersK.2001; Deletion of gene 52 encoding glycoprotein M of equine herpesvirus type 1 strain RacH results in increased immunogenicity. Vet Microbiol 81:219–226[CrossRef]
RoquemoreE. P.,
BantingG.1998; Efficient trafficking of TGN38 from the endosome to the trans -Golgi network requires a free hydroxyl group at position 331 in the cytosolic domain. Mol Biol Cell 9:2125–2144[CrossRef]
RossJ.,
WilliamsM.,
CohenJ. I.1997; Disruption of the varicella-zoster virus dUTPase and the adjacent ORF9A gene results in impaired growth and reduced syncytia formation in vitro. Virology 234:186–195[CrossRef]
RudolphJ.,
SeyboldtC.,
GranzowH.,
OsterriederN.2002; The gene 10 (UL49·5) product of equine herpesvirus 1 is necessary and sufficient for functional processing of glycoprotein M. J Virol 76:2952–2963[CrossRef]
TaylorG.,
StottE. J.,
FurzeJ.,
FordJ.,
SoppP.1992; Protective epitopes on the fusion protein of respiratory syncytial virus recognized by murine and bovine monoclonal antibodies. J Gen Virol 73:2217–2223[CrossRef]
TurnerA.,
BruunB.,
MinsonT.,
BrowneH.1998; Glycoproteins gB, gD, and gHgL of herpes simplex virus type 1 are necessary and sufficient to mediate membrane fusion in a Cos cell transfection system. J Virol 72:873–875
WarnerM. S.,
GeraghtyR. J.,
MartinezW. M.,
MontgomeryR. I.,
WhitbeckJ. C.,
XuR.,
EisenbergR. J.,
CohenG. H.,
SpearP. G.1998; A cell surface protein with herpesvirus entry activity (HveB) confers susceptibility to infection by mutants of herpes simplex virus type 1, herpes simplex virus type 2, and pseudorabies virus. Virology 246:179–189[CrossRef]
WuS. X.,
ZhuX. P.,
LetchworthG. J.1998; Bovine herpesvirus 1 glycoprotein M forms a disulfide-linked heterodimer with the UL49·5 protein. J Virol 72:3029–3036
YoungJ. F.,
DesselbergerU.,
GravesP.,
PaleseP.,
ShatzmanA.,
RosenbergM.1983; Cloning and expression of influenza virus genes. In The Origin of Viruses pp 129–138 Edited by
LaverW. G.
Amsterdam: Elsevier Science;
ZhaoX.,
GreenerT.,
Al-HasaniH.,
CushmanS. W.,
EisenbergE.,
GreeneL. E.2001; Expression of auxilin or AP180 inhibits endocytosis by mislocalizing clathrin: evidence for formation of nascent pits containing AP1 or AP2 but not clathrin. J Cell Sci 114:353–365