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Published online 18 September 2006. doi:10.1083/jcb.200603026
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 174, Number 7, 923-929
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 Higher order Rab programming in phagolysosome biogenesis

Esteban A. Roberts1, Jennifer Chua1, George B. Kyei1, and Vojo Deretic1,2

1 Department of Molecular Genetics and Microbiology and 2 Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, NM 87131

Correspondence to Vojo Deretic: vderetic{at}salud.unm.edu

Phagosomes offer kinetically and morphologically tractable organelles to dissect the control of phagolysosome biogenesis by Rab GTPases. Model phagosomes harboring latex beads undergo a coordinated Rab5–Rab7 exchange, which is akin to the process of endosomal Rab conversion, the control mechanisms of which are unknown. In the process of blocking phagosomal maturation, the intracellular pathogen Mycobacterium tuberculosis prevents Rab7 acquisition, thus, providing a naturally occurring tool to study Rab conversion. We show that M. tuberculosis inhibition of Rab7 acquisition and arrest of phagosomal maturation depends on Rab22a. Four-dimensional microscopy revealed that phagosomes harboring live mycobacteria recruited and retained increasing amounts of Rab22a. Rab22a knockdown in macrophages via siRNA enhanced the maturation of phagosomes with live mycobacteria. Conversely, overexpression of the GTP-locked mutant Rab22aQ64L prevented maturation of phagosomes containing heat-killed mycobacteria, which normally progress into phagolysosomes. Moreover, Rab22a knockdown led to Rab7 acquisition by phagosomes harboring live mycobacteria. Our findings show that Rab22a defines the critical checkpoint for Rab7 conversion on phagosomes, allowing or disallowing organellar transition into a late endosomal compartment. M. tuberculosis parasitizes this process by actively recruiting and maintaining Rab22a on its phagosome, thus, preventing Rab7 acquisition and blocking phagolysosomal biogenesis.

E.A. Roberts and J. Chua contributed equally to this paper.

Abbreviations used in this paper: 4D, four-dimensional; BCG, bacillus Calmette-Guérin.


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