title: Class B β-arrestin2-dependent CCR5 signalosome retention with natural antibodies to CCR5.
abstract: CCR5 stimulation with natural ligands, such as RANTES, classically induces short-term internalization with transient activation of β-arrestins and rapidly recycling on the cell surface. Here we discovered that, in T cells, natural CCR5 antibodies induce a CCR5-negative phenotype with the involvement of β-arrestin2, which leads to the formation of a stable CCR5 signalosome with both β-arrestin2 and ERK1. The activation of β-arrestin2 is necessary to CCR5 signaling for the signalosome formation and stabilization. When all stimuli were washed out, β-arrestin1 silencing favors the activity of β-arrestin2 for the CCR5 signalosome retention. Interestingly, CCR5 turn from Class A trafficking pattern, normally used for its internalization with natural modulating molecules (i.e. RANTES), into a long lasting Class B type specifically induced by stimulation with natural anti-CCR5 antibodies. This new CCR5 pathway is relevant not only to study in depth the molecular basis of all pathologies where CCR5 is involved but also to generate new antidody-based therapeutics.
authors.affiliation: Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, 20132, Italy.
authors.forename: Assunta
authors.initials: A
authors.lastname: Venuti
authors.affiliation: Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, 20132, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Pastori
authors.affiliation: Department of Chemical Biological Pharmaceutical and Environmental Sciences, University of Messina, Messina, 98166, Italy.
authors.forename: Rosamaria
authors.initials: R
authors.lastname: Pennisi
authors.affiliation: Third Division of Infectious Diseases, Luigi Sacco Hospital, University of Milan, Milan, 20157, Italy.
authors.forename: Agostino
authors.initials: A
authors.lastname: Riva
authors.affiliation: Department of Chemical Biological Pharmaceutical and Environmental Sciences, University of Messina, Messina, 98166, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Sciortino
authors.affiliation: Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, 20132, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Lopalco
mesh_terms: D000906:Antibodies / Q000378:metabolism*; D002460:Cell Line; D018946:Chemokine CCL5 / Q000378:metabolism; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D019713:Receptors, CCR5 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000378:metabolism; D000071560:beta-Arrestin 2 / Q000378:metabolism*
chemical_list: D000906:Antibodies; C584933:CCR5 protein, human; D018946:Chemokine CCL5; D019713:Receptors, CCR5; D000071560:beta-Arrestin 2; D020928:Mitogen-Activated Protein Kinases