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Human Cytomegalovirus Regulates Surface Expression of the Viral Protein UL18 by Means of Two Motifs Present in the Cytoplasmic Tail¹

Massimo Maffei^2,*, Fabio Ghiotto^2,*, Marzia Occhino^*, Maria Bono^*, Amleto De Santanna, Lorenzo Battini, G. Luca Gusella, Franco Fais^*, Silvia Bruno^3,* and Ermanno Ciccone^*

^* Human Anatomy Section and Histology Section, Department of Experimental Medicine, University of Genoa, Genova, Italy; and Division of Renal Medicine, Mount Sinai School of Medicine, New York, NY 10029

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 YXX 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from Compagnia di San Paolo, Ministero per l’Istruzione, l’Università e la Ricerca Scientifica, and Progetto Finalizzato Ministero della Salute (to E.C.).

² M.M. and F.G. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Silvia Bruno, Department of Experimental Medicine, Human Anatomy Section, University of Genoa, Via De Toni 14, 16132 Genova, Italy. E-mail address: silvia.bruno{at}unige.it

⁴ Abbreviations used in this paper used: HCMV, human cytomegalovirus; EGFP, enhanced GFP; EndoH, endoglycosidase H; ER, endoplasmic reticulum; GAM, goat anti-mouse; HFF, human foreskin fibroblast; MOI, multiplicity of infection; PNGaseF, peptide N-glycosidase F; PFA, paraformaldehyde; IP, immunoprecipitation.

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				M. Occhino, F. Ghiotto, S. Soro, M. Mortarino, S. Bosi, M. Maffei, S. Bruno, M. Nardini, M. Figini, A. Tramontano, et al. Dissecting the Structural Determinants of the Interaction between the Human Cytomegalovirus UL18 Protein and the CD85j Immune Receptor J. Immunol., January 15, 2008; 180(2): 957 - 968. [Abstract] [Full Text] [PDF]