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Mycoplasma promotes malignant transformation in vivo, and its DnaK, a bacterial chaperone protein, has broad
Davide Zella1,2, Sabrina Curreli3,4, Francesca Benedetti3,2
1Institute of Human Virology, School of Medicine, University of Maryland, Baltimore, MD 21201; dzella@ihv.umaryland.edu rgallo@ihv.umaryland.edu.
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.
Insights
Human mycoplasma infection promotes cancer by interfering with p53 activity and DNA repair. Bacterial DnaK protein disrupts key cellular pathways, impairing anticancer functions and drug efficacy.
Area of Science:
- Microbiology
- Oncology
- Molecular Biology
Background:
- Mycoplasma infection is linked to various diseases.
- The p53 tumor suppressor pathway is crucial for preventing cancer.
- Bacterial proteins can influence host cell functions.
Purpose of the Study:
- To investigate the mechanism by which mycoplasma promotes lymphomagenesis.
- To identify specific mycoplasma factors involved in cancer development.
- To understand how mycoplasma affects p53 activity and DNA repair.
Main Methods:
- Isolation of a human mycoplasma strain.
- In vitro infection of cells and SCID mice models.
- Immunoprecipitation to identify mycoplasma proteins interacting with p53.
- Analysis of mycoplasma DnaK interactions with human proteins (DNA-PK, PARP1, USP10).
- Phylogenetic analysis of bacterial DnaK proteins.
Main Results:
- Mycoplasma infection promoted lymphomagenesis in SCID mice via a p53-dependent mechanism.
- Mycoplasma DnaK was identified as a key protein interacting with p53 regulators and DNA repair enzymes.
- DnaK impaired p53-dependent anticancer functions, DNA repair, and reduced anticancer drug efficacy.
- Evidence suggests a 'hit-and-run/hide' mechanism and potential paracrine function of DnaK.
- Similar DnaK proteins in other cancer-associated bacteria suggest a common oncogenic mechanism.
Conclusions:
- Mycoplasma DnaK is a critical factor in bacterial oncogenesis.
- Disruption of DNA repair and p53 dysregulation are key mechanisms.
- This highlights a common bacterial strategy for promoting cancer and drug resistance.
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