A role for ARF6 in dendritic cell podosome formation and migration

Henrik G. Svensson, Michele A. West, Pamela Mollahan, Alan R. Prescott, Rossana Zaru, Colin Watts

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    29 Citations (Scopus)

    Abstract

    ADP-ribosylation factor 6 (ARF6) is a widely expressed GTPase that influences both membrane traffic and actin cytoskeleton function. Its role in dendritic cells (DC) has not previously been investigated. We analysed the effect of retroviral expression of ARF6 GDP/GTP binding and other functional mutants in primary murine DC. Maturation in response to lipopolysaccharide (LPS) proceeded normally in DC expressing ARF6 mutants and production of inflammatory cytokines was similarly unaffected. Although LPS-stimulated macropinocytosis was suppressed by expression of the GTP-binding Q67L ARF6 mutant we detected no overall activation of ARF6 by LPS. The ability of immature DC to migrate towards CCL3 and to a lesser extent, of mature DC to migrate towards CCL19, was compromised by expression of either the Q67L or the GDP-binding T44N mutant. Examination of the actin cytoskeleton in these cells revealed that both mutants strongly inhibited the formation of F-actin-rich podosomes, providing a possible explanation for the effects of ARF6 mutants on DC migration. Thus, these studies identify responses in DC that require normal ARF6 function, though not necessarily further ARF6 activation. They reveal for the first time a role for ARF6 in podosome formation and demonstrate functional effects of the T44N ARF6 mutant.

    Original languageEnglish
    Pages (from-to)818-828
    Number of pages11
    JournalEuropean Journal of Immunology
    Volume38
    Issue number3
    DOIs
    Publication statusPublished - Mar 2008

    Keywords

    • adhesion molecules
    • cell trafficking
    • dendritic cells
    • signal transduction
    • ADP-RIBOSYLATION FACTOR-6
    • RECEPTOR-MEDIATED PHAGOCYTOSIS
    • PLASMA-MEMBRANE
    • ACTIN CYTOSKELETON
    • IN-VIVO
    • ACTIVATION
    • MATURATION
    • GTPASE
    • RAC1
    • REQUIREMENT

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