ERK1-Based Pathway as a New Selective Mechanism To Modulate CCR5 with Natural Antibodies.
Natural human Abs, recognizing an epitope within the first extramembrane loop of CCR5 (the main HIV coreceptor), induce a long-lasting internalization (48 h) of the protein, whereas all known CCR5 modulating molecules show a short-term kinetics (60-90 min). Despite extensive studies on the regulation of CCR5 signaling cascades, which are the effect of concomitant CCR5 internalization by exogenous stimuli such as Abs, downstream signaling continues to be poorly understood. In this article, we report a hitherto unrecognized mechanism of CCR5 modulation mediated by G protein-dependent ERK1 activity. We further demonstrate that ERK1 is localized mainly in the cytoplasmic compartment and that it interacts directly with the CCR5 protein, thus provoking possible CCR5 degradation with a subsequent de novo synthesis, and that re-expression of CCR5 on the cell membrane required several days. In contrast, the RANTES treatment induces a recovery of the receptor on the cell membrane in short-term kinetics without the involvement of de novo protein synthesis. The said new pathway could be relevant not only to better understand the molecular basis of all pathologic conditions in which CCR5 is involved but also to generate new tools to block viral infections, such as the use of recombinant Abs.
Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20127 Milan, Italy;
Assunta
A
Venuti
Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20127 Milan, Italy;
Claudia
C
Pastori
Department of Biological and Environmental Sciences, University of Messina, 98166 Messina, Italy; and.
Gabriel
G
Siracusano
Third Division of Infectious Diseases, Luigi Sacco Hospital, University of Milan, 20157 Milan, Italy.
Agostino
A
Riva
Department of Biological and Environmental Sciences, University of Messina, 98166 Messina, Italy; and lopalco.lucia@hsr.it mtsciortino@unime.it.
Maria Teresa
MT
Sciortino
Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20127 Milan, Italy; lopalco.lucia@hsr.it mtsciortino@unime.it.
Lucia
L
Lopalco
D000906:Antibodies / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D018946:Chemokine CCL5 / Q000378:metabolism / Q000494:pharmacology*; D002966:Clathrin / Q000494:pharmacology; D000939:Epitopes / Q000276:immunology; D006801:Humans; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D021381:Protein Transport / Q000276:immunology; D034622:RNA Interference; D034741:RNA, Small Interfering; D019713:Receptors, CCR5 / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology
D000906:Antibodies; C483024:CCL5 protein, human; C584933:CCR5 protein, human; D018946:Chemokine CCL5; D002966:Clathrin; D000939:Epitopes; D034741:RNA, Small Interfering; D019713:Receptors, CCR5; D048052:Mitogen-Activated Protein Kinase 3