A Rab20-Dependent Membrane Trafficking Pathway Controls M. tuberculosis Replication by Regulating Phagosome Spaciousness and Integrity

• Published in: Cell host & microbe 2017-05, Vol.21 (5), p.619-628.e5
• Main Authors: Schnettger, Laura, Rodgers, Angela, Repnik, Urska, Lai, Rachel P., Pei, Gang, Verdoes, Martijn, Wilkinson, Robert J., Young, Douglas B., Gutierrez, Maximiliano G.
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Bacterial - metabolism; Bacterial Proteins - metabolism; Cell Culture Techniques; Disease Models, Animal; Endosomes - metabolism; Female; Host-Pathogen Interactions - physiology; Humans; Interferon-gamma - metabolism; macrophage; Macrophages - cytology; Macrophages - immunology; Macrophages - microbiology; Membranes - metabolism; Mice; Mice, Inbred C57BL; mycobacterium; Mycobacterium tuberculosis - growth & development; Mycobacterium tuberculosis - immunology; Mycobacterium tuberculosis - metabolism; Mycobacterium tuberculosis - pathogenicity; phagosome; Phagosomes - enzymology; Phagosomes - immunology; Phagosomes - metabolism; Phagosomes - microbiology; Protein Transport - physiology; rab GTP-Binding Proteins - metabolism; Rab GTPases; Rab20; RAW 264.7 Cells; Sequence Analysis, RNA; Short; Spatio-Temporal Analysis; Sputum; tuberculosis
• ISSN: 1931-3128; 1934-6069; 1934-6069
• DOI: 10.1016/j.chom.2017.04.004

The intracellular pathogen Mycobacterium tuberculosis (Mtb) lives within phagosomes and also disrupts these organelles to access the cytosol. The host pathways and mechanisms that contribute to maintaining Mtb phagosome integrity have not been investigated. Here, we examined the spatiotemporal dynamics of Mtb-containing phagosomes and identified an interferon-gamma-stimulated and Rab20-dependent membrane trafficking pathway in macrophages that maintains Mtb in spacious proteolytic phagolysosomes. This pathway functions to promote endosomal membrane influx in infected macrophages, and is required to preserve Mtb phagosome integrity and control Mtb replication. Rab20 is specifically and significantly upregulated in the sputum of human patients with active tuberculosis. Altogether, we uncover an immune-regulated cellular pathway of defense that promotes maintenance of Mtb within intact membrane-bound compartments for efficient elimination. [Display omitted] •The spatiotemporal dynamics of the M. tuberculosis (Mtb) phagosome were investigated•A Rab20-dependent pathway regulates endocytic influx into Mtb phagosomes•Mtb avoids targeting to Rab20-positive phagosomes through its ESX-1 system•Rab20 is required to maintain Mtb phagosome integrity and for control of Mtb replication Host-dependent mechanisms that regulate the M. tuberculosis (Mtb) phagosome are unexplored. Schnettger et al. investigate the spatiotemporal dynamics of Mtb phagosomes and identify an IFN-γ-stimulated, Rab20-dependent membrane trafficking pathway in macrophages that maintains Mtb in spacious proteolytic phagolysosomes and is required for mycobacterial control.