title: Slit2N/Robo1 inhibit HIV-gp120-induced migration and podosome formation in immature dendritic cells by sequestering LSP1 and WASp.
abstract: Cell-mediated transmission and dissemination of sexually-acquired human immunodeficiency virus 1 (HIV-1) in the host involves the migration of immature dendritic cells (iDCs). iDCs migrate in response to the HIV-1 envelope protein, gp120, and inhibiting such migration may limit the mucosal transmission of HIV-1. In this study, we elucidated the mechanism of HIV-1-gp120-induced transendothelial migration of iDCs. We found that gp120 enhanced the binding of Wiskott-Aldrich Syndrome protein (WASp) and the Actin-Related Protein 2/3 (Arp2/3) complex with β-actin, an interaction essential for the proper formation of podosomes, specialized adhesion structures required for the migration of iDCs through different tissues. We further identified Leukocyte-Specific Protein 1 (LSP1) as a novel component of the WASp-Arp2/3-β-actin complex. Pretreating iDCs with an active fragment of the secretory glycoprotein Slit2 (Slit2N) inhibited HIV-1-gp120-mediated migration and podosome formation, by inducing the cognate receptor Roundabout 1 (Robo1) to bind to and sequester WASp and LSP1 from β-actin. Slit2N treatment also inhibited Src signaling and the activation of several downstream molecules, including Rac1, Pyk2, paxillin, and CDC42, a major regulator of podosome formation. Taken together, our results support a novel mechanism by which Slit2/Robo1 may inhibit the HIV-1-gp120-induced migration of iDCs, thereby restricting dissemination of HIV-1 from mucosal surfaces in the host.
authors.affiliation: Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Anil
authors.initials: A
authors.lastname: Prasad
authors.forename: Paula M
authors.initials: PM
authors.lastname: Kuzontkoski
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Shrivastava
authors.forename: Weiquan
authors.initials: W
authors.lastname: Zhu
authors.forename: Dean Y
authors.initials: DY
authors.lastname: Li
authors.forename: Jerome E
authors.initials: JE
authors.lastname: Groopman
mesh_terms: D051376:Actin-Related Protein 2-3 Complex / Q000276:immunology / Q000378:metabolism; D000199:Actins / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D051418:Focal Adhesion Kinase 2 / Q000276:immunology / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000276:immunology* / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology* / Q000378:metabolism; D008840:Microfilament Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018613:Microscopy, Confocal; D009419:Nerve Tissue Proteins / Q000276:immunology* / Q000378:metabolism; D051419:Paxillin / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000276:immunology / Q000378:metabolism; D011554:Pseudopodia / Q000276:immunology; D034622:RNA Interference; D011971:Receptors, Immunologic / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D051316:Wiskott-Aldrich Syndrome Protein / Q000276:immunology* / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000276:immunology / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000276:immunology / Q000378:metabolism; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein
chemical_list: D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; D051418:Focal Adhesion Kinase 2; D015699:HIV Envelope Protein gp120; D036341:Intercellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D051419:Paxillin; D016392:Proto-Oncogene Proteins pp60(c-src); D011971:Receptors, Immunologic; D051316:Wiskott-Aldrich Syndrome Protein; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein; C489183:LSP1 protein, human