The functions and inhibitors of protein tyrosine phosphatase B from Mycobacterium tuberculosis.

Mycobacterium tuberculosis (Mtb) secretes the low molecular weight protein tyrosine phosphatase B (PtpB), which disrupts key host innate immune defenses. This review synthesizes current knowledge regarding PtpB, highlighting its unique structural features, including a ubiquitin-activated dynamic lid that regulates its catalytic activity toward diverse substrates. PtpB is known to suppress pro-inflammatory cytokine production by dephosphorylating essential components of the MAPK and JAK-STAT signaling pathways. Additionally, upon activation by host ubiquitin, PtpB directly dephosphorylates plasma membrane lipids such as phosphatidylinositol 4-phosphate (PI4P) and phosphatidylinositol 4,5-bisphosphate [PI (4,5)P2], thereby inhibiting the plasma membrane localization of gasdermin D and blocking pyroptosis. This review further evaluates the translational potential of targeting PtpB, emphasizing the discovery and structural characterization of potent, selective inhibitors. Ultimately, PtpB emerges as an attractive target for novel host-directed therapies against tuberculosis, especially in the face of rising drug resistance.