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First published online August 24, 2006
doi: 10.1242/10.1242/jcs.03091

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cAMP synthesis and degradation by phagosomes regulate actin assembly and fusion events: consequences for mycobacteria

Stefanos A. Kalamidas^1,2,*, Mark P. Kuehnel^1,*,, Pascale Peyron^1,3, Vladimir Rybin¹, Susanne Rauch¹, Othon B. Kotoulas², Miles Houslay⁴, Brian A. Hemmings⁵, Maximiliano G. Gutierrez⁶, Elsa Anes⁷ and Gareth Griffiths¹

¹ EMBL, Postfach 102209, 69117 Heidelberg, Germany
² Department of Anatomy, Histology and Embryology, Medical School, University of Ioannina, Ioannina 45 110, Greece
³ Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique, Toulouse 31077, France
⁴ Division Biochemistry and Molecular Biology, IBLS, Wolfson Building, University of Glasgow, Glasgow, Scotland, UK
⁵ Friedrich Miescher Institute for Biomedical Research, Basel 4058, Switzerland
⁶ Laboratorio de Biología Celular y Molecular, IHEM-CONICET, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza 5500, Argentina
⁷ Molecular Pathogenesis Centre, Faculty of Pharmacy, University of Lisbon, Av. Forcas Armadas, 1600-083 Lisbon, Portugal

Author for correspondence (e-mail:kuehnel{at}embl.de)

Accepted 9 June 2006

We showed recently that actin assembly by phagosomal membranes facilitates fusion with late endocytic organelles in macrophages. Moreover, lipids that induced phagosomal actin also stimulated this fusion process. In macrophages infected with pathogenic mycobacteria actin-stimulatory lipids led to an increase in pathogen destruction, whereas inhibitors facilitated their growth. A model was proposed whereby phagosomal membrane actin assembly provides tracks for lysosomes to move towards phagosomes, thereby facilitating fusion. Here, we investigated how cAMP affected phagosomal actin assembly in vitro, and phagosomal actin, acidification and late fusion events in J774 macrophages. Latex bead phagosomes are shown to possess adenylyl cyclase activity, which synthesizes cAMP, and phosphodiesterase activity, which degrades cAMP. The system is regulated by protein kinase A (PKA). Increasing cAMP levels inhibited, whereas decreasing cAMP levels stimulated, actin assembly in vitro and within cells. Increasing cAMP levels also inhibited phagosome-lysosome fusion and acidification in cells, whereas reducing cAMP had the opposite effect. High cAMP levels induced an increase in intraphagosomal growth in macrophages of both the non-pathogenic Mycobacterium smegmatis and the pathogenic Mycobacterium tuberculosis, whereas low cAMP levels or inhibition of PKA correlated with increased bacterial destruction. We argue that the phagosome cAMP-PKA system behaves as a molecular switch that regulates phagosome actin and maturation in macrophages.

Key words: cAMP, Actin, Mycobacteria, Phagosomes

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