Human cytomegalovirus regulates surface expression of the viral protein UL18 by means of two motifs present in the cytoplasmic tail.
UL18 is a trans-membrane viral protein expressed on human cytomegalovirus (HCMV)-infected cells, and its surface expression determines the interaction of infected cells with lymphocytes expressing the CD85j (LIR-1/ILT2) receptor. We previously showed that the UL18-CD85j interaction elicits activation of T lymphocytes. However, in in vitro cell models UL18 displays mostly undetectable surface expression. Thus, we asked how surface expression of UL18 is regulated. Domain-swapping experiments and construction of specific mutants demonstrated that two motifs on its cytoplasmic tail, homologous to YXXPhi and KKXX consensus sequences, respectively, are responsible for impairing UL18 surface expression. However, the presence of the whole HCMV genome, granted by HCMV infection of human fibroblasts, restored surface expression of either UL18 or chimeric proteins carrying the UL18 cytoplasmic tail, starting from the third day after infection. It is of note that the two motifs responsible for cytoplasmic retention are identical in all 17 HCMV strains examined. We disclosed a control mechanism used by the HCMV to regulate the availability of UL18 on the infected-cell surface to allow interaction with its ligand on T and NK cells.
Maffei
Massimo
M
Human Anatomy Section, Department of Experimental Medicine, University of Genoa, Genova, Italy.
Ghiotto
Fabio
F
Occhino
Marzia
M
Bono
Maria
M
De Santanna
Amleto
A
Battini
Lorenzo
L
Gusella
G Luca
GL
Fais
Franco
F
Bruno
Silvia
S
Ciccone
Ermanno
E
D020816:Amino Acid Motifs / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D036022:Capsid Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D016384:Consensus Sequence; D003587:Cytomegalovirus / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000737:chemistry / Q000378:metabolism; D005347:Fibroblasts; D016679:Genome, Viral; D006056:Golgi Apparatus / Q000737:chemistry / Q000378:metabolism; D015789:HLA-A2 Antigen / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D011993:Recombinant Fusion Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism
D036022:Capsid Proteins; D015789:HLA-A2 Antigen; D011993:Recombinant Fusion Proteins; C079750:VP23 protein, Human herpesvirus 1