title: Mycobacterium tuberculosis protein tyrosine phosphatase (PtpA) excludes host vacuolar-H+-ATPase to inhibit phagosome acidification.
abstract: Mycobacterium tuberculosis (Mtb) pathogenicity depends on its ability to inhibit phagosome acidification and maturation processes after engulfment by macrophages. Here, we show that the secreted Mtb protein tyrosine phosphatase (PtpA) binds to subunit H of the macrophage vacuolar-H(+)-ATPase (V-ATPase) machinery, a multisubunit protein complex in the phagosome membrane that drives luminal acidification. Furthermore, we show that the macrophage class C vacuolar protein sorting complex, a key regulator of endosomal membrane fusion, associates with V-ATPase in phagosome maturation, suggesting a unique role for V-ATPase in coordinating phagosome-lysosome fusion. PtpA interaction with host V-ATPase is required for the previously reported dephosphorylation of VPS33B and subsequent exclusion of V-ATPase from the phagosome during Mtb infection. These findings show that inhibition of phagosome acidification in the mycobacterial phagosome is directly attributed to PtpA, a key protein needed for Mtb survival and pathogenicity within host macrophages.
authors.affiliation: Department of Medicine, Division of Infectious Diseases,  University of British Columbia, Vancouver, BC,  Canada V5Z 3J5.
authors.forename: Dennis
authors.initials: D
authors.lastname: Wong
authors.forename: Horacio
authors.initials: H
authors.lastname: Bach
authors.forename: Jim
authors.initials: J
authors.lastname: Sun
authors.forename: Zakaria
authors.initials: Z
authors.lastname: Hmama
authors.forename: Yossef
authors.initials: Y
authors.lastname: Av-Gay
mesh_terms: D003001:Cloning, Molecular; D005822:Genetic Vectors; D006863:Hydrogen-Ion Concentration; D008856:Microscopy, Fluorescence; D009000:Monocytes / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000472:pathogenicity; D010588:Phagosomes / Q000737:chemistry* / Q000378:metabolism; D025941:Protein Interaction Mapping; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism*
chemical_list: D017027:Protein Tyrosine Phosphatases; D025262:Vacuolar Proton-Translocating ATPases
references.citation: Mol Biol Cell. 2011 Apr 15;22(8):1353-63
references.pmid: 21325627
references.citation: J Exp Med. 1996 Oct 1;184(4):1349-55
references.pmid: 8879207
references.citation: J Biol Chem. 2010 Sep 17;285(38):29239-46
references.pmid: 20630871
references.citation: Annu Rev Cell Dev Biol. 2005;21:511-27
references.pmid: 16212505
references.citation: Curr Opin Cell Biol. 2009 Aug;21(4):543-51
references.pmid: 19577915
references.citation: Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7134-9
references.pmid: 11416198
references.citation: Science. 2010 May 14;328(5980):856-61
references.pmid: 20466923
references.citation: J Biol Chem. 1997 Nov 21;272(47):29810-20
references.pmid: 9368053
references.citation: Physiol Rev. 1997 Jul;77(3):759-803
references.pmid: 9234965
references.citation: Biochim Biophys Acta. 2010 Mar;1804(3):620-7
references.pmid: 19766738
references.citation: Mol Biol Cell. 1997 Nov;8(11):2307-27
references.pmid: 9362071
references.citation: PLoS Pathog. 2010 Mar 19;6(3):e1000822
references.pmid: 20333253
references.citation: J Microbiol Methods. 2008 May;73(2):79-84
references.pmid: 18387683
references.citation: Microb Pathog. 1999 Oct;27(4):253-63
references.pmid: 10502466
references.citation: Res Microbiol. 2002 May;153(4):233-41
references.pmid: 12066895
references.citation: Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):15190-5
references.pmid: 10611360
references.citation: Nat Rev Mol Cell Biol. 2007 Nov;8(11):917-29
references.pmid: 17912264
references.citation: Infect Immun. 2006 Dec;74(12):6540-6
references.pmid: 16982836
references.citation: J Biol Chem. 2002 Aug 9;277(32):28521-9
references.pmid: 12032142
references.citation: Cytometry A. 2010 Mar;77(3):243-52
references.pmid: 19937952
references.citation: Dev Cell. 2007 May;12(5):739-50
references.pmid: 17488625
references.citation: FEBS Lett. 2008 Apr 30;582(10):1558-63
references.pmid: 18405665
references.citation: Bioinformatics. 2008 May 1;24(9):1137-44
references.pmid: 18326508
references.citation: Infect Immun. 2003 Oct;71(10):5514-22
references.pmid: 14500469
references.citation: Cell Host Microbe. 2008 May 15;3(5):316-22
references.pmid: 18474358
references.citation: Bioessays. 2000 Mar;22(3):255-63
references.pmid: 10684585
references.citation: Mol Cell. 2007 Apr 27;26(2):165-74
references.pmid: 17466620
references.citation: J Cell Biol. 2000 Oct 30;151(3):551-62
references.pmid: 11062257
references.citation: J Leukoc Biol. 2007 Dec;82(6):1437-45
references.pmid: 18040083
references.citation: Science. 1994 Feb 4;263(5147):678-81
references.pmid: 8303277
references.citation: Biochem J. 2009 May 13;420(2):155-60
references.pmid: 19366344
references.citation: Eur J Cell Biol. 1996 Apr;69(4):343-50
references.pmid: 8741216
references.citation: FEMS Microbiol Rev. 2005 Nov;29(5):1041-50
references.pmid: 16040149
references.citation: Cell Microbiol. 2010 Aug;12(8):1046-63
references.pmid: 20148899
references.citation: Cell. 2005 May 20;121(4):607-620
references.pmid: 15907473
references.citation: Trends Microbiol. 2000 May;8(5):238-44
references.pmid: 10785641
references.citation: Anal Biochem. 1998 Jan 1;255(1):127-32
references.pmid: 9448851
references.citation: PLoS Pathog. 2010 May 06;6(5):e1000895
references.pmid: 20463815
references.citation: J Cell Sci. 2009 Jul 15;122(Pt 14):2504-13
references.pmid: 19549681
references.citation: J Biol Chem. 2003 May 30;278(22):19791-7
references.pmid: 12651853
references.citation: Curr Biol. 2005 Feb 22;15(4):360-5
references.pmid: 15723798