Rab14 is critical for maintenance of Mycobacterium tuberculosis phagosome maturation arrest

George B. Kyei, Isabelle Vergne, Jennifer Chua, Esteban Roberts, James Harris, Jagath R. Junutula, Vojo Deretic

Research output: Contribution to journalArticleResearchpeer-review

121 Citations (Scopus)

Abstract

Mycobacterium tuberculosis arrests phagosomal maturation in infected macrophage, and, apart from health significance, provides a superb model system to dissect the phagolysosomal biogenesis pathway. Here, we demonstrate a critical role for the small GTPase Rab14 in maintaining mycobacterial phagosome maturation block. Four-dimensional microscopy showed that phagosomes containing live mycobacteria accumulated Rab14 following phagocytosis. The recruitment of Rab14 had strong functional consequence, as a knockdown of endogenous Rab14 by siRNA or overexpression of Rab14 dominant-negative mutants (Rab14S25N and Rab14N125I) released the maturation block and allowed phagosomes harboring live mycobacteria to progress into phagolysosomes. Conversely, overexpression of the wild-type Rab14 and the constitutively active mutant Rab14Q70L prevented phagosomes with dead mycobacteria from undergoing default maturation into phagolysosomal organelles. Mechanistic studies demonstrated a role for Rab14 in stimulating organellar fusion between phagosomes and early endosomes but not with late endosomes. Rab14 enables mycobacterial phagosomes to maintain early endosomal characteristics and avoid late endosomal/lysosomal degradative components.

Original languageEnglish
Pages (from-to)5250-5259
Number of pages10
JournalThe EMBO Journal
Volume25
Issue number22
DOIs
Publication statusPublished - 15 Nov 2006
Externally publishedYes

Keywords

  • Endosome
  • Lysosome
  • Phagosome
  • Rab
  • Tuberculosis

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