Dynamic partitioning into lipid rafts controls the endo-exocytic cycle of the αL/β2 integrin, LFA-1, during leukocyte chemotaxis

Monica Fabbri, Silvia Di Meglio, Maria Cristina Gagliani, Elisa Consonni, Raffaella Molteni, Jeffrey R. Bender, Carlo Tacchetti, Ruggero Pardi

Research output: Contribution to journalArticle

Abstract

Cell migration entails the dynamic redistribution of adhesion receptors from the cell rear toward the cell front, where they form new protrusions and adhesions. This process may involve regulated endo-exocytosis of integrins. Here we show that in primary neutrophils unengaged αL/β2 integrin (LFA-1) is internalized and rapidly recycled upon chemoattractant stimulation via a clathrin-independent, cholesterol-sensitive pathway involving dynamic partitioning into detergent-resistant membranes (DRM). Persistent DRM association is required for recycling of the internalized receptor because 1) >90% of endocytosed LFA-1 is associated with DRM, and a large fraction of the internalized receptor colocalizes intracellularly with markers of DRM and the recycling endocytic compartment; 2) a recycling-defective mutant (αL/β2 Y735A) dissociates rapidly from DRM upon being endocytosed and is subsequently diverted into a late endosomal pathway; and 3) a dominant negative Rab11 mutant (Rab11S25N) induces intracellular accumulation of endocytosed αL/β2 and prevents its enrichment in chemoattractant-induced lamellipodia. Notably, chemokine-induced migration of neutrophils over immobilized ICAM-1 is abrogated by cholesterol-sequestering agents. We propose that DRM-associated endocytosis allows efficient retrieval of integrins, as they detach from their ligands, followed by polarized recycling to areas of the plasma membrane, such as lamellipodia, where they establish new adhesive interactions and promote outside-in signaling events.

Original languageEnglish
Pages (from-to)5793-5803
Number of pages11
JournalMolecular Biology of the Cell
Volume16
Issue number12
DOIs
Publication statusPublished - Dec 2005

    Fingerprint

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this