Mycobacterium tuberculosis Mce2E suppresses the macrophage innate immune response and promotes epithelial cell proliferation

Cell Mol Immunol. 2019 Apr;16(4):380-391. doi: 10.1038/s41423-018-0016-0. Epub 2018 Mar 23.

Abstract

The intracellular pathogen Mycobacterium tuberculosis (Mtb) can survive in the host and cause disease by interfering with a variety of cellular functions. The mammalian cell entry 2 (mce2) operon of Mtb has been shown to contribute to tuberculosis pathogenicity. However, little is known about the regulatory roles of Mtb Mce2 family proteins towards host cellular functions. Here we show that the Mce2 family protein Mce2E suppressed the macrophage innate immune response and promoted epithelial cell proliferation. Mce2E inhibited activation of the extracellular signal-regulated kinase (ERK) and Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) signaling pathways in a non-canonical D motif (a MAPK-docking motif)-dependent manner, leading to reduced expression of TNF and IL-6 in macrophages. Furthermore, Mce2E promoted proliferation of human lung epithelium-derived lung adenoma A549 cells by inhibiting K48-linked polyubiquitination of eEF1A1 in a β strand region-dependent manner. In summary, Mce2E is a novel multifunctional Mtb virulence factor that regulates host cellular functions in a niche-dependent manner. Our data suggest a potential novel target for TB therapy.

Keywords: Mce2E; Mycobacterium tuberculosis; cell proliferation; innate immune response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs / genetics
  • Animals
  • Antigens, Bacterial / genetics
  • Antigens, Bacterial / metabolism
  • Antigens, Bacterial / physiology*
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Bacterial Proteins / physiology*
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Cytokines / metabolism
  • Epithelial Cells / metabolism*
  • Female
  • Humans
  • Immunity, Innate
  • MAP Kinase Signaling System* / genetics
  • MAP Kinase Signaling System* / immunology
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Nude
  • Mycobacterium tuberculosis / immunology*
  • Mycobacterium tuberculosis / pathogenicity
  • Peptide Elongation Factor 1 / metabolism
  • Transplantation, Heterologous
  • Tuberculosis / immunology*
  • Ubiquitination / genetics
  • Ubiquitination / immunology
  • Virulence Factors / metabolism

Substances

  • Antigens, Bacterial
  • Bacterial Proteins
  • Cytokines
  • Eef1a1 protein, mouse
  • Peptide Elongation Factor 1
  • Virulence Factors
  • mce2 protein, Mycobacterium tuberculosis