Essential role of elmo1 in dock2-dependent lymphocyte migration (CAM1P.228)

Abstract

Abstract Elmo1 and Elmo2 are highly homologous cytoplasmic adapter 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. Here 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. Lymphocytes from Elmo1-/- mice showed a four-fold reduction in total Dock2 protein levels despite normal levels of Dock2 mRNA, suggesting Elmo1 is critical for the maintenance of Dock2 levels in primary lymphocytes. Indeed, Dock2 polyubiquitination was increased in Elmo1-/- T cells, and treatment with proteasome inhibitors partially restored Dock2 levels in Elmo1-/- T cells. Taken together, these findings reveal a previously unknown, non-redundant role for Elmo1 in controlling Dock2 levels and Dock2-dependent T cell migration. This work provides valuable insights into the molecular regulation of Dock2 by Elmo1 that can be used to design improved Dock2-based therapeutic approaches.