title: Essential role of Elmo1 in Dock2-dependent lymphocyte migration.
abstract: Elmo1 and Elmo2 are highly homologous cytoplasmic adaptor proteins that interact with Dock family guanine nucleotide exchange factors to promote activation of the small GTPase Rac. In T lymphocytes, Dock2 is essential for CCR7- and CXCR4-dependent Rac activation and chemotaxis, but the role of Elmo proteins in regulating Dock2 function in primary T cells is not known. In this article, we show that endogenous Elmo1, but not Elmo2, interacts constitutively with Dock2 in mouse and human primary T cells. CD4(+) T cells from Elmo1(-/-) mice were profoundly impaired in polarization, Rac activation, and chemotaxis in response to CCR7 and CXCR4 stimulation. Transfection of full-length Elmo1, but not Elmo2 or a Dock2-binding mutant of Elmo1, rescued defective migration of Elmo1(-/-) T cells. Interestingly, Dock2 protein levels were reduced by 4-fold in Elmo1(-/-) lymphocytes despite normal levels of Dock2 mRNA. Dock2 polyubiquitination was increased in Elmo1(-/-) T cells, and treatment with proteasome inhibitors partially restored Dock2 levels in Elmo1(-/-) T cells. Finally, we show that Dock2 is directly ubiquitinated in CD4(+) T cells and that Elmo1 expression in heterologous cells inhibits ubiquitination of Dock2. Taken together, these findings reveal a previously unknown, nonredundant role for Elmo1 in controlling Dock2 levels and Dock2-dependent T cell migration in primary lymphocytes. Inhibition of Dock2 has therapeutic potential as a means to control recruitment of pathogenic lymphocytes in diseased tissues. This work provides valuable insights into the molecular regulation of Dock2 by Elmo1 that can be used to design improved inhibitors that target the Elmo-Dock-Rac signaling complex.
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642; and David H. Smith Center for Vaccine Biology and Imunology, University of Rochester Medical Center, Rochester, NY 14642.
authors.forename: Catherine
authors.initials: C
authors.lastname: Stevenson
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642; and David H. Smith Center for Vaccine Biology and Imunology, University of Rochester Medical Center, Rochester, NY 14642.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: de la Rosa
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642; and David H. Smith Center for Vaccine Biology and Imunology, University of Rochester Medical Center, Rochester, NY 14642.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Anderson
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642; and David H. Smith Center for Vaccine Biology and Imunology, University of Rochester Medical Center, Rochester, NY 14642.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Murphy
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642; and David H. Smith Center for Vaccine Biology and Imunology, University of Rochester Medical Center, Rochester, NY 14642.
authors.forename: Tara
authors.initials: T
authors.lastname: Capece
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642; and David H. Smith Center for Vaccine Biology and Imunology, University of Rochester Medical Center, Rochester, NY 14642.
authors.forename: Minsoo
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642; and David H. Smith Center for Vaccine Biology and Imunology, University of Rochester Medical Center, Rochester, NY 14642 michael_elliott@urmc.rochester.edu.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Elliott
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000276:immunology*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000276:immunology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D054400:Receptors, CCR7 / Q000235:genetics / Q000276:immunology; D019718:Receptors, CXCR4 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D054875:Ubiquitination / Q000235:genetics / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C515370:CCR7 protein, human; C527276:CXCR4 protein, human; C514936:CXCR4 protein, mouse; C515371:Ccr7 protein, mouse; C402110:DOCK2 protein, human; C471356:DOCK2 protein, mouse; C465214:ELMO1 protein, human; C510359:ELMO1 protein, mouse; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D054400:Receptors, CCR7; D019718:Receptors, CXCR4