The Journal of Experimental Medicine
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Published 18 August 2003. doi:10.1084/jem.20030527
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© Rockefeller University Press, 0022-1007/2003/8/653 $5.00
The Journal of Experimental Medicine, Volume 198, Number 4, 653-659

Brief Definitive Report

Tuberculosis Toxin Blocking Phagosome Maturation Inhibits a Novel Ca2+/Calmodulin-PI3K hVPS34 Cascade

Isabelle Vergne1, Jennifer Chua1,2 and Vojo Deretic1

1 Department of Molecular Genetics and Microbiology and Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, NM 87131
2 Program in Biomedical Sciences, University of Michigan Medical School, Ann Arbor, MI 48109

Address correspondence to Vojo Deretic, Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, NM 87131. Phone: 505-272-0291; Fax: 505-272-5309; email: vderetic{at}salud.unm.edu

The capacity of Mycobacterium tuberculosis to infect latently over one billion people and cause two million fatalities annually rests with its ability to block phagosomal maturation into the phagolysosome in infected macrophages. Here we describe how M. tuberculosis toxin lipoarabinomannan (LAM) causes phagosome maturation arrest, interfering with a new pathway connecting intracellular signaling and membrane trafficking. LAM from virulent M. tuberculosis, but not from avirulent mycobacteria, blocked cytosolic Ca2+ increase. Ca2+ and calmodulin were required for a newly uncovered Ca2+/calmodulin phosphatidylinositol (PI)3 kinase hVPS34 cascade, essential for production of PI 3 phosphate (PI3P) on liposomes in vitro and on phagosomes in vivo. The interference of the trafficking toxin LAM with the calmodulin-dependent production of PI3P described here ensures long-term M. tuberculosis residence in vacuoles sequestered away from the bactericidal and antigen-processing organelles in infected macrophages.

Key Words: phosphatidylinositol 3-kinase • calmodulin • calcium • Mycobacterium tuberculosis • EEA1


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