Mycobacterial Tyrosine Phosphatase PtpB Affects Host Cytokine Expression by Dephosphorylating ERK1/2 and STAT3

TL;DR

This study shows how the Mycobacterium tuberculosis enzyme PtpB reduces inflammation by altering key signaling proteins in host cells.

Contribution

First comprehensive mapping of PtpA and PtpB substrate effects on host phosphorylation and cytokine regulation.

Findings

PtpB decreases phosphorylation of ERK1/2 and STAT3 in host cells.

PtpB suppresses cytokine production by inhibiting ERK1/2 nuclear translocation and disrupting JAK/STAT signaling.

In vivo experiments show PtpB enhances bacterial survival while reducing cytokine expression.

Abstract

Mycobacterium tuberculosis (Mtb) tyrosine phosphatases PtpA and PtpB have been widely reported to affect host immunity response and bacterial intercellular survival. However, a comprehensive investigation into the impact of PtpA and PtpB on host phosphorylation, specifically in their roles as tyrosine phosphatases, has not yet been reported. In this study, we first conducted the potential dephosphorylation substrates map of PtpA and PtpB within the host. Our findings demonstrated that PtpB significantly decreased the phosphorylation levels of ERK1/2 and STAT3. Subsequent analysis indicated that PtpB modulated the production of cytokine TNF and IL-1β by dephosphorylating ERK1/2 and preventing its nuclear translocation. PtpB also reduced IL-6 and IL-1β expression by dephosphorylating STAT3. The in vivo experiment demonstrated increased bacterial survival and reduced cytokine expression in the PtpB-overexpression strain. Consequently, our findings demonstrate that Mtb tyrosine phosphatases PtpA and PtpB play critical roles in the global tyrosine phosphorylation landscape within the host. Specifically, PtpB modulates cytokine expression through the dephosphorylation of ERK1/2 and STAT3.

•First comprehensive characterization of the substrate landscape of Mycobacterium phosphatases PtpA and PtpB in host cells.•PtpB inhibits nuclear translocation of ERK1/2 via dephosphorylation, thereby suppressing host cytokine expression.•PtpB reduces IL-6 expression by disrupting host JAK/STAT signaling pathways.

First comprehensive characterization of the substrate landscape of Mycobacterium phosphatases PtpA and PtpB in host cells.

PtpB inhibits nuclear translocation of ERK1/2 via dephosphorylation, thereby suppressing host cytokine expression.

PtpB reduces IL-6 expression by disrupting host JAK/STAT signaling pathways.

This study comprehensively characterizes the substrate landscape of Mycobacterium tyrosine phosphatases PtpA and PtpB within host systems. We demonstrate that PtpB suppresses ERK1/2-mediated cytokine expression by reducing ERK1/2 phosphorylation and inhibiting its nuclear translocation. Furthermore, PtpB downregulates STAT3 phosphorylation, thereby impairing JAK-STAT signaling and subsequent IL-6 cytokine secretion. These findings were validated in both cellular and animal models.

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