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PNAS 103 (48): 18226-18231

Copyright © 2006 by the National Academy of Sciences.


Immunoglobulin G signaling activates lysosome/phagosome docking

Vishal Trivedi*, Shao C. Zhang*, Adam B. Castoreno*, Walter Stockinger*, Eugenie C. Shieh*, Jatin M. Vyas{dagger}, Eva-Maria Frickel{ddagger}, and Axel Nohturfft*,§

*Department of Molecular and Cellular Biology, Biological Laboratories, Harvard University, 16 Divinity Avenue, Cambridge, MA 02138; {dagger}Division of Infectious Disease, Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114; and {ddagger}Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142

Communicated by Richard M. Losick, Harvard University, Cambridge, MA, October 17, 2006

Received for publication August 16, 2006.

Abstract: An important role of IgG antibodies in the defense against microbial infections is to promote the ingestion and killing of microbes by phagocytes. Here, we developed in vivo and in vitro approaches to ask whether opsonization of particles with IgG enhances intracellular targeting of lysosomes to phagosomes. To eliminate the effect of IgG on the ingestion process, cells were exposed to latex beads at 15–20°C, which allows engulfment of both IgG-coated and uncoated beads but prevents the fusion of lysosomes with phagosomes. Upon shifting the temperature to 37°C, phagosomes containing IgG beads matured significantly faster into phagolysosomes as judged by colocalization with lysosomal markers. The IgG effect was independent of other particle-associated antigens or serum factors. Lysosome/phagosome attachment was also quantified biochemically with a cytosol-dependent scintillation proximity assay. Interactions were enhanced significantly in reactions containing cytosol from mouse macrophages that had been exposed to IgG-coated beads, indicating that IgG signaling modulates the cytosolic-targeting machinery. Similar results were obtained with cytosol from primary human monocytes, human U-937 histiocytic lymphoma cells and from Chinese hamster ovary (CHO) cells transfected with a human IgG (Fc{gamma}) receptor. IgG-induced activation is shown to affect the actin-dependent tethering/docking stage of the targeting process and to proceed through a pathway involving protein kinase C. These results provide a rare example of an extracellular signal controlling membrane targeting on the level of tethering and docking. We propose that this pathway contributes to the role of antibodies in the protection against microbial infections.

Key Words: membrane fusion • protein kinase C • scintillation proximity assay • Fc receptor • macrophages

Author contributions: V.T. and A.N. designed research; V.T., S.C.Z., E.C.S., and A.N. performed research; V.T., A.B.C., W.S., J.M.V., and E.-M.F. contributed new reagents/analytic tools; V.T., S.C.Z., E.C.S., and A.N. analyzed data; and V.T. and A.N. wrote the paper.

The authors declare no conflict of interest.

§To whom correspondence should be addressed. E-mail: axno{at}

© 2006 by The National Academy of Sciences of the USA

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