Mechanism of Phagolysosome Biogenesis Block by Viable Mycobacterium Tuberculosis

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2005 Mar 9

PMID 15753315

Citations 231

Authors

Isabelle Vergne

Jennifer Chua

Hwang-Ho Lee

Megan Lucas

John Belisle

Vojo Deretic

Affiliations

Soon will be listed here.

Abstract

Live Mycobacterium tuberculosis persists in macrophage phagosomes by interfering with phagolysosome biogenesis. Here, using four-dimensional microscopy and in vitro assays, we report the principal difference between phagosomes containing live and dead mycobacteria. Phosphatidylinositol 3-phosphate (PI3P), a membrane trafficking regulatory lipid essential for phagosomal acquisition of lysosomal constituents, is retained on phagosomes harboring dead mycobacteria but is continuously eliminated from phagosomes with live bacilli. We show that the exclusion of PI3P from live mycobacterial phagosomes can be only transiently reversed by Ca2+ fluxes, and that live M. tuberculosis secretes a lipid phosphatase, SapM, that hydrolyzes PI3P, inhibits phagosome-late endosome fusion in vitro, and contributes to inhibition of phagosomal maturation.

Citing Articles

Advances in Host-Pathogen Interactions in Tuberculosis: Emerging Strategies for Therapeutic Intervention.

Nasiri M, Venketaraman V Int J Mol Sci. 2025; 26(4).

PMID: 40004082 PMC: 11855387. DOI: 10.3390/ijms26041621.

Long non-coding RNA transcripts in -host interactions.

Vijayaraghavan M, Gadad S, Dhandayuthapani S Noncoding RNA Res. 2025; 11:281-293.

PMID: 39926616 PMC: 11803167. DOI: 10.1016/j.ncrna.2024.12.005.

Toward Virulence Inhibition: Beyond Cell Wall.

Kotliarova M, Shumkov M, Goncharenko A Microorganisms. 2025; 13(1).

PMID: 39858789 PMC: 11767696. DOI: 10.3390/microorganisms13010021.

Mucosal immune response in biology, disease prevention and treatment.

Zhou X, Wu Y, Zhu Z, Lu C, Zhang C, Zeng L Signal Transduct Target Ther. 2025; 10(1):7.

PMID: 39774607 PMC: 11707400. DOI: 10.1038/s41392-024-02043-4.

Combating Tuberculosis via Restoring the Host Immune Capacity by Targeting Kinases and Phosphatases.

Alsayed S, Gunosewoyo H Int J Mol Sci. 2024; 25(22).

PMID: 39596546 PMC: 11595174. DOI: 10.3390/ijms252212481.

References

Petiot A, Ogier-Denis E, Blommaart E, Meijer A, Codogno P . Distinct classes of phosphatidylinositol 3'-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells. J Biol Chem. 2000; 275(2):992-8. DOI: 10.1074/jbc.275.2.992. View

Simonsen A, Lippe R, Christoforidis S, Gaullier J, Brech A, Callaghan J . EEA1 links PI(3)K function to Rab5 regulation of endosome fusion. Nature. 1998; 394(6692):494-8. DOI: 10.1038/28879. View

Maehama T, Taylor G, Slama J, Dixon J . A sensitive assay for phosphoinositide phosphatases. Anal Biochem. 2000; 279(2):248-50. DOI: 10.1006/abio.2000.4497. View

Clemens D, Lee B, Horwitz M . Deviant expression of Rab5 on phagosomes containing the intracellular pathogens Mycobacterium tuberculosis and Legionella pneumophila is associated with altered phagosomal fate. Infect Immun. 2000; 68(5):2671-84. PMC: 97474. DOI: 10.1128/IAI.68.5.2671-2684.2000. View

Siddhanta U, McIlroy J, Shah A, Zhang Y, Backer J . Distinct roles for the p110alpha and hVPS34 phosphatidylinositol 3'-kinases in vesicular trafficking, regulation of the actin cytoskeleton, and mitogenesis. J Cell Biol. 1998; 143(6):1647-59. PMC: 2132989. DOI: 10.1083/jcb.143.6.1647. View

Gutierrez M, Master S, Singh S, Taylor G, Colombo M, Deretic V . Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell. 2004; 119(6):753-66. DOI: 10.1016/j.cell.2004.11.038. View

Rojas M, Garcia L, Nigou J, Puzo G, Olivier M . Mannosylated lipoarabinomannan antagonizes Mycobacterium tuberculosis-induced macrophage apoptosis by altering Ca+2-dependent cell signaling. J Infect Dis. 2000; 182(1):240-51. DOI: 10.1086/315676. View

Taylor G, Maehama T, Dixon J . Myotubularin, a protein tyrosine phosphatase mutated in myotubular myopathy, dephosphorylates the lipid second messenger, phosphatidylinositol 3-phosphate. Proc Natl Acad Sci U S A. 2000; 97(16):8910-5. PMC: 16795. DOI: 10.1073/pnas.160255697. View

Gillooly D, Morrow I, Lindsay M, Gould R, Bryant N, Gaullier J . Localization of phosphatidylinositol 3-phosphate in yeast and mammalian cells. EMBO J. 2000; 19(17):4577-88. PMC: 302054. DOI: 10.1093/emboj/19.17.4577. View

10.

Koul A, Choidas A, Treder M, Tyagi A, Drlica K, Singh Y . Cloning and characterization of secretory tyrosine phosphatases of Mycobacterium tuberculosis. J Bacteriol. 2000; 182(19):5425-32. PMC: 110985. DOI: 10.1128/JB.182.19.5425-5432.2000. View

11.

Saleh M, Belisle J . Secretion of an acid phosphatase (SapM) by Mycobacterium tuberculosis that is similar to eukaryotic acid phosphatases. J Bacteriol. 2000; 182(23):6850-3. PMC: 111434. DOI: 10.1128/JB.182.23.6850-6853.2000. View

12.

Wishart M, Taylor G, Slama J, Dixon J . PTEN and myotubularin phosphoinositide phosphatases: bringing bioinformatics to the lab bench. Curr Opin Cell Biol. 2001; 13(2):172-81. DOI: 10.1016/s0955-0674(00)00195-2. View

13.

Kanai F, Liu H, Field S, Akbary H, Matsuo T, Brown G . The PX domains of p47phox and p40phox bind to lipid products of PI(3)K. Nat Cell Biol. 2001; 3(7):675-8. DOI: 10.1038/35083070. View

14.

Taylor G, Dixon J . An assay for phosphoinositide phosphatases utilizing fluorescent substrates. Anal Biochem. 2001; 295(1):122-6. DOI: 10.1006/abio.2001.5179. View

15.

Fratti R, Backer J, Gruenberg J, Corvera S, Deretic V . Role of phosphatidylinositol 3-kinase and Rab5 effectors in phagosomal biogenesis and mycobacterial phagosome maturation arrest. J Cell Biol. 2001; 154(3):631-44. PMC: 2196432. DOI: 10.1083/jcb.200106049. View

16.

Vieira O, Botelho R, Rameh L, Brachmann S, Matsuo T, Davidson H . Distinct roles of class I and class III phosphatidylinositol 3-kinases in phagosome formation and maturation. J Cell Biol. 2001; 155(1):19-25. PMC: 2150784. DOI: 10.1083/jcb.200107069. View

17.

Walker D, Urbe S, Dove S, Tenza D, Raposo G, Clague M . Characterization of MTMR3. an inositol lipid 3-phosphatase with novel substrate specificity. Curr Biol. 2001; 11(20):1600-5. DOI: 10.1016/s0960-9822(01)00501-2. View

18.

Pereira-Leal J, Seabra M . Evolution of the Rab family of small GTP-binding proteins. J Mol Biol. 2001; 313(4):889-901. DOI: 10.1006/jmbi.2001.5072. View

19.

Russell D, Mwandumba H, Rhoades E . Mycobacterium and the coat of many lipids. J Cell Biol. 2002; 158(3):421-6. PMC: 2173834. DOI: 10.1083/jcb.200205034. View

20.

Katzmann D, Odorizzi G, Emr S . Receptor downregulation and multivesicular-body sorting. Nat Rev Mol Cell Biol. 2002; 3(12):893-905. DOI: 10.1038/nrm973. View