Hematopoietic lineage cell-specific protein 1 functions in concert with the Wiskott-Aldrich syndrome protein to promote podosome array organization and chemotaxis in dendritic cells

Deborah A.Klos Dehring, Fiona Clarke, Brendon G. Ricart, Yanping Huang, Timothy S. Gomez, Edward K. Williamson, Daniel A. Hammer, Daniel D. Billadeau, Yair Argon, Janis K. Burkhardt

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Dendritic cells (DCs) are professional APCs that reside in peripheral tissues and survey the body for pathogens. Upon activation by inflammatory signals, DCs undergo a maturation process and migrate to lymphoid organs, where they present pathogen-derived Ags to T cells. DC migration depends on tight regulation of the actin cytoskeleton to permit rapid adaptation to environmental cues. We investigated the role of hematopoietic lineage cell-specific protein 1 (HS1), the hematopoietic homolog of cortactin, in regulating the actin cytoskeleton of murine DCs. HS1 localized to lamellipodial protrusions and podosomes, actin-rich structures associated with adhesion and migration. DCs from HS1-/- mice showed aberrant lamellipodial dynamics. Moreover, although these cells formed recognizable podosomes, their podosome arrays were loosely packed and improperly localized within the cell. HS1 interacts with Wiskott-Aldrich syndrome protein (WASp), another key actin-regulatory protein, through mutual binding to WASp-interacting protein. Comparative analysis of DCs deficient for HS1, WASp or both proteins revealed unique roles for these proteins in regulating podosomes with WASp being essential for podosome formation and with HS1 ensuring efficient array organization. WASp recruitment to podosome cores was independent of HS1, whereas HS1 recruitment required Src homology 3 domain-dependent interactions with the WASp/WASp-interacting protein heterodimer. In migration assays, the phenotypes of HS1-and WASp-deficient DCs were related, but distinct. WASp-/y DCs migrating in a chemokine gradient showed a large decrease in velocity and diminished directional persistence. In contrast, HS1-/- DCs migrated faster than wild-type cells, but directional persistence was significantly reduced. These studies show that HS1 functions in concert with WASp to fine-tune DC cytoarchitecture and direct cell migration.

Original languageEnglish (US)
Pages (from-to)4805-4818
Number of pages14
JournalJournal of Immunology
Volume186
Issue number8
DOIs
StatePublished - Apr 15 2011

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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