title: Dedicator of cytokinesis 8 interacts with talin and Wiskott-Aldrich syndrome protein to regulate NK cell cytotoxicity.
abstract: Recently, patients with mutations in DOCK8 have been reported to have a combined immunodeficiency characterized by cutaneous viral infections and allergies. NK cells represent a first-line defense against viral infections, suggesting that DOCK8 might participate in NK cell function. In this study, we demonstrate that DOCK8-suppressed human NK cells showed defects in natural cytotoxicity as well as specific activating receptor-mediated NK cytotoxicity. Additionally, compared with control NK cells, NK cells depleted of DOCK8 showed defective conjugate formation, along with decreased polarization of LFA-1, F-actin, and cytolytic granules toward the cytotoxic synapse. Using a proteomic approach, we found that DOCK8 exists in a macromolecular complex with the Wiskott-Aldrich syndrome protein, an actin nucleation-promoting factor activated by CDC42, as well as talin, which is required for integrin-mediated adhesion. Taken together, our results demonstrate an important role for DOCK8 in NK cell effector function and provide important new mechanistic insight into how DOCK8 regulates F-actin and integrin-mediated adhesion in immune cells.
authors: Department of Immunology, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
authors: Hyoungjun
authors: H
authors: Ham
authors: Sabrice
authors: S
authors: Guerrier
authors: JungJin
authors: J
authors: Kim
authors: Renee A
authors: RA
authors: Schoon
authors: Erik L
authors: EL
authors: Anderson
authors: Michael J
authors: MJ
authors: Hamann
authors: Zhenkun
authors: Z
authors: Lou
authors: Daniel D
authors: DD
authors: Billadeau
mesh_terms: D000199:Actins / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D003594:Cytoplasmic Granules / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D015870:Gene Expression; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D008954:Models, Biological; D011485:Protein Binding; D016608:Talin / Q000378:metabolism*; D051316:Wiskott-Aldrich Syndrome Protein / Q000378:metabolism*
chemical_list: D000199:Actins; C516591:DOCK8 protein, human; D020662:Guanine Nucleotide Exchange Factors; D016169:Lymphocyte Function-Associated Antigen-1; D016608:Talin; D051316:Wiskott-Aldrich Syndrome Protein