Journal
JOURNAL OF CELL BIOLOGY
Volume 184, Issue 2, Pages 281-296Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200806121
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Funding
- National Institutes of Health [P50-GM21681, R01-GM06110, R01-NS056049, R01-CA03922-24, R01-HL083392, PO1-HL40387, R01-DK069633]
- Robert A. Welch Foundation [I-1200]
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he actin cytoskeleton is dynamically remodeled during Fc gamma receptor (Fc gamma R)-mediated phagocytosis in a phosphatidylinositol (4,5)-bisphosphate (PIP2)-dependent manner. We investigated the role of type I phosphatidylinositol 4-phosphate 5-kinase (PIP5K) gamma and alpha isoforms, which synthesize PIP 2, during phagocytosis. PIP5K-gamma-/- bone marrow-derived macrophages (BMM) have a highly polymerized actin cytoskeleton and are defective in attachment to IgG-opsonized particles and Fc gamma R clustering. Delivery of exogenous PIP2 rescued these defects. PIP5K-gamma knockout BMM also have more RhoA and less Rac1 activation, and pharmacological manipulations establish that they contribute to the abnormal phenotype. Likewise, depletion of PIP5K-gamma by RNA interference inhibits particle attachment. In contrast, PIP5K-alpha knockout or silencing has no effect on attachment but inhibits ingestion by decreasing Wiskott-Aldrich syndrome protein activation, and hence actin polymerization, in the nascent phagocytic cup. In addition, PIP5K-gamma but not PIP5K-alpha is transiently activated by spleen tyrosine kinase-mediated phosphorylation. We propose that PIP5K-gamma acts upstream of Rac/Rho and that the differential regulation of PIP5K-gamma and -alpha allows them to work in tandem to modulate the actin cytoskeleton during the attachment and ingestion phases of phagocytosis.
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