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A more recent version of this article appeared on November 1, 2005
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Submitted on July 19, 2005
Revised on August 8, 2005
Accepted on August 12, 2005
*CIHR Group in Matrix Dynamics, University of Toronto, Toronto, Ontario M5S 3E2, Canada; Molecular and Cellular Pharmacology Program, Department of Pharmacology, University of Wisconsin-Madison, Madison, WI 53706; Department of Physiology, Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA 19104
Monitoring Editor: Anthony Bretscher
Collagen phagocytosis is a critical mediator of extracellular matrix remodeling. Whereas the binding step of collagen phagocytosis is facilitated by Ca2+-dependent, gelsolin-mediated severing of actin filaments, the regulation of the collagen internalization step is not defined. We determined here if phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) regulation of gelsolin is required for collagen internalization. In gelsolin null fibroblasts transfected with gelsolin severing mutants, actin severing and collagen binding were strongly impaired but internalization and actin monomer addition at collagen bead sites were much less affected. PI(4,5)P2 accumulated around collagen during internalization and was associated with gelsolin. Cell-permeable peptides mimicking the PI(4,5)P2 binding site of gelsolin blocked actin monomer addition, the association of gelsolin with actin at phagosomes and collagen internalization but did not affect collagen binding. Collagen beads induced recruitment of type 1 
phosphatidylinositol phosphate kinase (PIPK1661) to internalization sites. Dominant negative constructs and RNAi demonstrated a requirement for catalytically active PIPK1661 for collagen internalization. We conclude that separate functions of gelsolin mediate sequential stages of collagen phagocytosis: Ca2+-dependent actin severing facilitates collagen binding while PI(4,5)P2-dependent regulation of gelsolin promotes the actin assembly required for internalization of collagen fibrils.
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