The mycobacterial phosphatase PtpA regulates the expression of host genes and promotes cell proliferation

Jing Wang,Dongdong Zhao,Rongbin Zhou,Lihua Qiang,Pupu Ge,Feng Tian,Mingzhao Zhu,Guangxun Meng,Cui Hua Liu,George Fu Gao,Qiyao Chai,Yoichiro Iwakura

doi:10.1038/s41467-017-00279-z

Abstract

Mycobacterium tuberculosis PtpA is a secreted effector protein that dephosphorylates several proteins in the host cell cytoplasm, such as p-JNK, p-p38, and p-VPS33B, leading to suppression of host innate immunity. Here we show that, in addition, PtpA enters the nucleus of host cells and regulates the expression of host genes, some of which are known to be involved in host innate immunity or in cell proliferation and migration (such as GADD45A). PtpA can bind directly to the promoter region of GADD45A in vitro. Both phosphatase activity and DNA-binding ability of PtpA are important in suppressing host innate immune responses. Furthermore, PtpA-expressing Mycobacterium bovis BCG promotes proliferation and migration of human lung adenoma A549 cells in vitro and in a mouse xenograft model. Further research is needed to test whether mycobacteria, via PtpA, might affect cell proliferation or migration in humans.

Highlights

Mycobacterium tuberculosis PtpA is a secreted effector protein that dephosphorylates several proteins in the host cell cytoplasm, such as p-JNK, p-p38, and p-VPS33B, leading to suppression of host innate immunity
With an aim to probe the subcellular location of PtpA in host cells, we performed confocal microscopy experiments using different Bacillus Calmette-Guerin (BCG) strains including wild-type (WT) BCG, PtpA-deleted BCG (BCG ΔPtpA), BCG ΔPtpA complemented with WT PtpA (ΔPtpA + PtpA) and BCG ΔPtpA complemented with phosphatase-inactive PtpA (ΔPtpA + D126A)
Our results indicated that some PtpA, but not PtpB, entered the nucleus of human macrophage-like U937 cells during BCG infection, and that this nuclear localization was independent of the phosphatase activity of PtpA (Fig. 1a)

Summary

Introduction

Mycobacterium tuberculosis PtpA is a secreted effector protein that dephosphorylates several proteins in the host cell cytoplasm, such as p-JNK, p-p38, and p-VPS33B, leading to suppression of host innate immunity. PtpA can bind directly to the promoter region of GADD45A in vitro Both phosphatase activity and DNA-binding ability of PtpA are important in suppressing host innate immune responses. PtpA-expressing Mycobacterium bovis BCG promotes proliferation and migration of human lung adenoma A549 cells in vitro and in a mouse xenograft model. Mtb PtpA can suppress the activation of NF-κB by competitively binding to the Npl[4] zinc-finger domain of TAB3 independently of its phosphatase activity[9] Those previous studies were mainly focused on the regulatory function of Mtb PtpA in the cytoplasm of host cells. PtpA-expressing Mycobacterium bovis Bacillus Calmette-Guerin (BCG) promotes cell proliferation and migration of a human lung adenoma cell line in vitro and in a mouse xenograft model. Further research is needed to test whether mycobacteria, via PtpA, might affect cell proliferation or migration in humans

Methods

Results

Conclusion