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J. Biol. Chem., Vol. 279, Issue 35, 36982-36992, August 27, 2004

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Mycobacterium tuberculosis Reprograms Waves of Phosphatidylinositol 3-Phosphate on Phagosomal Organelles^*

Jennifer Chua and Vojo Deretic¶

From the Departments of Molecular Genetics and Microbiology and Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131 and the Program in Biomedical Sciences, University of Michigan Medical School, Ann Arbor, Michigan 48109

The potent human pathogen Mycobacterium tuberculosis persists in macrophages within a specialized, immature phagosome by interfering with the pathway of phagolysosome biogenesis. The molecular mechanisms underlying this process remain to be fully elucidated. Here, using four-dimensional microscopy, we detected on model phagosomes, which normally mature into phagolysosomes, the existence of cyclical waves of phosphatidylinositol 3-phosphate (PI3P), a membrane trafficking regulatory lipid essential for phagosomal acquisition of lysosomal characteristics. We show that mycobacteria interfere with the dynamics of PI3P on phagosomal organelles by altering the timing and characteristics of the PI3P waves on phagosomes. The default program of cyclical PI3P waves on model phagosomes is composed of an initial stage (phase I), represented by a strong PI3P burst occurring only upon the completion of phagosome formation, and a subsequent stage (phase II) of recurring PI3P waves on maturing phagosomes with the average periodicity of 20 min. Mycobacteria alter this program in two ways: (i) by inducing, in a cholesterol-dependent fashion, a neophase I^* of premature PI3P production, coinciding with the process of mycobacterial entry into the macrophage, and (ii) by inhibiting the calmodulin-dependent phase II responsible for the acquisition of lysosomal characteristics. We conclude that the default pathway of phagosomal maturation into the phagolysosome includes temporally organized cyclical waves of PI3P on phagosomal membranes and that this process is targeted for reprogramming by mycobacteria as they prevent phagolysosome formation.

Received for publication, May 7, 2004 , and in revised form, June 16, 2004.

^* This work was supported by National Institutes of Health Grant AI45148. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Movies 1-4.

^¶ To whom correspondence should be addressed: Depts. of Molecular Genetics and Microbiology and Cell Biology and Physiology, University of New Mexico School of Medicine, 915 Camino de Salud, NE, Albuquerque, NM 87131. Tel.: 505-272-0291; Fax: 505-272-5309; E-mail: vderetic{at}salud.unm.edu.

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