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.

Mycobacterium tuberculosis Mce3E Suppresses Host Innate Immune Responses by Targeting ERK1/2 Signaling

“…Several effector proteins from pathogenic bacteria were shown to mimick host proteins such as phosphatases or kinases to evade host immune defenses (33,35,(49)(50)(51). Because Mce3E has a DEF motif and could interact with ERK1/2 directly, we initially examined whether Mce3E could be able to dephosphorylate p-ERK directly, but we were not able to demonstrate the phosphatase activity of Mce3E toward p-ERK in vitro.…”

The innate immune response in human tuberculosis

“…After phagocytosis, Mtb blocks phagosome acidification as well acquisition of hydrolytic enzymes and anti‐microbial peptides. Two major Mtb virulence factors are involved in the blockage of the phagosomal maturation in human cell lines: the glycolipid lipoarabinomannan (LAM) (Hmama et al ., 2004; Kang et al ., 2005; Welin et al ., 2008) and the secreted tyrosine phosphatase (PtpA) (Bach et al ., 2008; Wong et al ., 2011; Wong and Jacobs, 2011). Mtb lacking the surface lipid trehalose dimycolate (TDM) failed to block phagosome maturation in mouse macrophages (Katti et al ., 2008) but to date, this has not been shown in human cells.…”

Mycobacterium tuberculosis Promotes Anti-apoptotic Activity of the Macrophage by PtpA Protein-dependent Dephosphorylation of Host GSK3α

“…We have previously shown that the low molecular weight tyrosine phosphatase, PtpA, is needed to block phagosome maturation and is essential for M. tuberculosis pathogenicity within human macrophages (8). PtpA's substrate in the host is the human vesicle trafficking protein vacuolar protein sorting 33B (hVPS33B) (8,9), which plays a key role in the regulation of membrane fusion in the endocytic pathway (10).…”

“…PtpA's substrate in the host is the human vesicle trafficking protein vacuolar protein sorting 33B (hVPS33B) (8,9), which plays a key role in the regulation of membrane fusion in the endocytic pathway (10). Dephosphorylation of hVPS33B by PtpA translates directly into phagosome maturation arrest (8).…”