title: Regulation of CXCR4 conformation by the small GTPase Rac1: implications for HIV infection.
abstract: The chemokine receptor CXCR4 is a critical regulator of cell migration and serves as a coreceptor for HIV-1. The chemokine stromal cell derived factor-1, also known as CXCL12, binds to CXCR4 and exerts its biologic functions partly through the small guanosine triphosphate hydrolase (GTPase) Rac1 (ras-related C3 botulinum toxin substrate 1). We show in different cell types, including CD34(+) hematopoietic stem and progenitor cells, that inhibition of Rac1 causes a reversible conformational change in CXCR4, but not in the related receptors CXCR7 or CCR5. Biochemical experiments showed that Rac1 associates with CXCR4. The conformational change of CXCR4 on Rac1 inhibition blocked receptor internalization and impaired CXCL12-induced Gα(i) protein activation. Importantly, we found that the conformation adopted by CXCR4 after Rac1 inhibition prevents HIV-1 infection of both the U87-CD4-CXCR4 cell line and of primary peripheral blood mononuclear cells. In conclusion, our data show that Rac1 activity is required to maintain CXCR4 in the responsive conformation that allows receptor signaling and facilitates HIV-1 infection; this implies that Rac1 positively regulates CXCR4 function and identifies the Rac1-CXCR4 axis as a new target for preventing HIV-1 infection.
authors.affiliation: Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Younes
authors.initials: Y
authors.lastname: Zoughlami
authors.forename: Carlijn
authors.initials: C
authors.lastname: Voermans
authors.forename: Kim
authors.initials: K
authors.lastname: Brussen
authors.forename: Karel A
authors.initials: KA
authors.lastname: van Dort
authors.forename: Neeltje A
authors.initials: NA
authors.lastname: Kootstra
authors.forename: David
authors.initials: D
authors.lastname: Maussang
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Smit
authors.forename: Peter L
authors.initials: PL
authors.lastname: Hordijk
authors.forename: Paula B
authors.initials: PB
authors.lastname: van Hennik
mesh_terms: D057809:HEK293 Cells; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation / Q000187:drug effects; D019718:Receptors, CXCR4 / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D010455:Peptides; D019718:Receptors, CXCR4; D020830:rac1 GTP-Binding Protein