Dedicator of cytokinesis 8 interacts with talin and Wiskott-Aldrich syndrome protein to regulate NK cell cytotoxicity

J Immunol. 2013 Apr 1;190(7):3661-9. doi: 10.4049/jimmunol.1202792. Epub 2013 Mar 1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Cell Line
  • Cells, Cultured
  • Cytoplasmic Granules / metabolism
  • Cytotoxicity, Immunologic* / genetics
  • Gene Expression
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Humans
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism*
  • Lymphocyte Function-Associated Antigen-1 / metabolism
  • Models, Biological
  • Protein Binding
  • Talin / metabolism*
  • Wiskott-Aldrich Syndrome Protein / metabolism*

Substances

  • Actins
  • DOCK8 protein, human
  • Guanine Nucleotide Exchange Factors
  • Lymphocyte Function-Associated Antigen-1
  • Talin
  • Wiskott-Aldrich Syndrome Protein