Mycoplasma promotes malignant transformation in vivo, and its DnaK, a bacterial chaperone protein, has broad oncogenic properties

Proc Natl Acad Sci U S A. 2018 Dec 18;115(51):E12005-E12014. doi: 10.1073/pnas.1815660115. Epub 2018 Dec 3.

Abstract

We isolated a strain of human mycoplasma that promotes lymphomagenesis in SCID mice, pointing to a p53-dependent mechanism similar to lymphomagenesis in uninfected p53-/- SCID mice. Additionally, mycoplasma infection in vitro reduces p53 activity. Immunoprecipitation of p53 in mycoplasma-infected cells identified several mycoplasma proteins, including DnaK, a member of the Hsp70 chaperon family. We focused on DnaK because of its ability to interact with proteins. We demonstrate that mycoplasma DnaK interacts with and reduces the activities of human proteins involved in critical cellular pathways, including DNA-PK and PARP1, which are required for efficient DNA repair, and binds to USP10 (a key p53 regulator), impairing p53-dependent anticancer functions. This also reduced the efficacy of anticancer drugs that depend on p53 to exert their effect. mycoplasma was detected early in the infected mice, but only low copy numbers of mycoplasma DnaK DNA sequences were found in some primary and secondary tumors, pointing toward a hit-and-run/hide mechanism of transformation. Uninfected bystander cells took up exogenous DnaK, suggesting a possible paracrine function in promoting malignant transformation, over and above cells infected with the mycoplasma. Phylogenetic amino acid analysis shows that other bacteria associated with human cancers have similar DnaKs, consistent with a common mechanism of cellular transformation mediated through disruption of DNA-repair mechanisms, as well as p53 dysregulation, that also results in cancer-drug resistance. This suggests that the oncogenic properties of certain bacteria are DnaK-mediated.

Keywords: DNA repair; DnaK; cancer; mycoplasma; p53.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / classification
  • Adenosine Triphosphatases / genetics*
  • Animals
  • Antineoplastic Agents / therapeutic use
  • Bacterial Proteins / classification
  • Bacterial Proteins / genetics*
  • Carcinogenesis / genetics*
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • DNA Repair
  • DNA, Bacterial / genetics
  • DNA-Activated Protein Kinase / metabolism
  • Disease Models, Animal
  • Genes, Bacterial / genetics
  • HCT116 Cells
  • HSP70 Heat-Shock Proteins / metabolism
  • Humans
  • Lymphoma / genetics
  • Lymphoma / microbiology
  • Lymphoma / pathology
  • Mice
  • Mice, SCID
  • Molecular Chaperones / classification
  • Molecular Chaperones / genetics*
  • Mycoplasma / genetics*
  • Mycoplasma / pathogenicity
  • Mycoplasma Infections / microbiology
  • Mycoplasma fermentans / genetics
  • Mycoplasma fermentans / pathogenicity
  • Oncogenes
  • Phylogeny
  • Poly (ADP-Ribose) Polymerase-1 / metabolism
  • Sequence Analysis
  • Sequence Analysis, Protein
  • Tumor Suppressor Protein p53 / metabolism
  • Ubiquitin Thiolesterase / metabolism

Substances

  • Antineoplastic Agents
  • Bacterial Proteins
  • DNA, Bacterial
  • HSP70 Heat-Shock Proteins
  • Molecular Chaperones
  • Tumor Suppressor Protein p53
  • USP10 protein, mouse
  • PARP1 protein, human
  • Parp1 protein, mouse
  • Poly (ADP-Ribose) Polymerase-1
  • DNA-Activated Protein Kinase
  • Ubiquitin Thiolesterase
  • Adenosine Triphosphatases
  • DnaK protein, Brevibacillus choshinensis