Mycobacterium tuberculosis virulence is mediated by PtpA dephosphorylation of human vacuolar protein sorting 33B

Cell Host Microbe. 2008 May 15;3(5):316-22. doi: 10.1016/j.chom.2008.03.008.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Gene Deletion
  • Humans
  • Lysosomes / metabolism
  • Macrophages / microbiology*
  • Mycobacterium tuberculosis / enzymology*
  • Mycobacterium tuberculosis / pathogenicity*
  • Phagosomes / microbiology
  • Phosphorylation
  • Protein Tyrosine Phosphatases / genetics
  • Protein Tyrosine Phosphatases / metabolism*
  • Tuberculosis / microbiology*
  • Vesicular Transport Proteins / metabolism*
  • Virulence


  • VPS33B protein, human
  • Vesicular Transport Proteins
  • Protein Tyrosine Phosphatases