title: Mycobacterium tuberculosis virulence is mediated by PtpA dephosphorylation of human vacuolar protein sorting 33B.
abstract: Entry into host macrophages and evasion of intracellular destruction mechanisms, including phagosome-lysosome fusion, are critical elements of Mycobacterium tuberculosis (Mtb) pathogenesis. To achieve this, the Mtb genome encodes several proteins that modify host signaling pathways. PtpA, a low-molecular weight tyrosine phosphatase, is a secreted Mtb protein of unknown function. The lack of tyrosine kinases in the Mtb genome suggests that PtpA may modulate host tyrosine phosphorylated protein(s). We report that a genetic deletion of ptpA attenuates Mtb growth in human macrophages, and expression of PtpA-neutralizing antibodies simulated this effect. We identify VPS33B, a regulator of membrane fusion, as a PtpA substrate. VPS33B and PtpA colocalize in Mtb-infected human macrophages. PtpA secretion combined with active-phosphorylated VPS33B inhibited phagosome-lysosome fusion, a process arrested in Mtb infections. These results demonstrate that PtpA is essential for Mtb intracellular persistence and identify a key host regulatory pathway that is inactivated by Mtb.
authors.affiliation: Department of Medicine, Division of Infectious Diseases, University of British Columbia, Vancouver, British Columbia V5Z 3J5, Canada.
authors.forename: Horacio
authors.initials: H
authors.lastname: Bach
authors.forename: Kadamba G
authors.initials: KG
authors.lastname: Papavinasasundaram
authors.forename: Dennis
authors.initials: D
authors.lastname: Wong
authors.forename: Zakaria
authors.initials: Z
authors.lastname: Hmama
authors.forename: Yossef
authors.initials: Y
authors.lastname: Av-Gay
mesh_terms: D017353:Gene Deletion; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000382:microbiology*; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000472:pathogenicity*; D010588:Phagosomes / Q000382:microbiology; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D014376:Tuberculosis / Q000382:microbiology*; D033921:Vesicular Transport Proteins / Q000378:metabolism*; D014774:Virulence
chemical_list: C411584:VPS33B protein, human; D033921:Vesicular Transport Proteins; D017027:Protein Tyrosine Phosphatases