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Multitarget mechanism of MYC inhibition by the bacterial lon protease in disease

Ambite, Ines LU orcid ; Wan, Murphy Lam Yim LU ; Tran, Hien Thi LU ; Nazari, Atefeh LU ; Chaudhuri, Arunima LU orcid ; Krintel, Christian LU ; Gomes, Inês ; Sabari, Samudra LU ; Ahmadi, Shahram LU and Carneiro, António N.B.M. , et al. (2025) In Scientific Reports 15(1).
Abstract

Identifying specific inhibitors of the MYC oncogene has been challenging, due to off target effects associated with MYC inhibition. This study investigated how the recombinant Escherichia coli Lon protease (rLon), which targets MYC in human cells, inhibits MYC over-activation in models of infection and cancer. In silico predictions identified specific peptide domains of bacterial Lon that target MYC and the affinity of these peptides for MYC was investigated by surface plasmon resonance. The N-terminal domain of rLon was shown to interact with the C-terminal, leucine zipper domain of MYC and MAX and to prevent MYC/MAX dimerization. Furthermore, rLon targeted and degraded c-MYC in vitro and in cellular models, through the peptidase... (More)

Identifying specific inhibitors of the MYC oncogene has been challenging, due to off target effects associated with MYC inhibition. This study investigated how the recombinant Escherichia coli Lon protease (rLon), which targets MYC in human cells, inhibits MYC over-activation in models of infection and cancer. In silico predictions identified specific peptide domains of bacterial Lon that target MYC and the affinity of these peptides for MYC was investigated by surface plasmon resonance. The N-terminal domain of rLon was shown to interact with the C-terminal, leucine zipper domain of MYC and MAX and to prevent MYC/MAX dimerization. Furthermore, rLon targeted and degraded c-MYC in vitro and in cellular models, through the peptidase domain. In a model of kidney infection, rLon treatment prevented, c-MYC, N-MYC and L-MYC over-expression, MYC-dependent gene expression, specifically renal toxicity genes and pathology, suggesting that rLon recognizes and corrects MYC dysregulation in this disease. The findings describe a multitarget mechanism of MYC inhibition by rLon, and the combined effects achieved by the Lon domains, targeting different MYC epitopes and MYC-dependent functions, with no evidence of toxicity or detrimental effects on homeostatic MYC expression.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Scientific Reports
volume
15
issue
1
article number
6778
publisher
Nature Publishing Group
external identifiers
  • pmid:40000737
  • scopus:85219186257
ISSN
2045-2322
DOI
10.1038/s41598-025-88093-2
language
English
LU publication?
yes
id
9b7af5b0-b04a-4ddf-83e7-9a7dfba8dc7b
date added to LUP
2025-06-10 08:37:50
date last changed
2025-07-08 11:34:41
@article{9b7af5b0-b04a-4ddf-83e7-9a7dfba8dc7b,
  abstract     = {{<p>Identifying specific inhibitors of the MYC oncogene has been challenging, due to off target effects associated with MYC inhibition. This study investigated how the recombinant Escherichia coli Lon protease (rLon), which targets MYC in human cells, inhibits MYC over-activation in models of infection and cancer. In silico predictions identified specific peptide domains of bacterial Lon that target MYC and the affinity of these peptides for MYC was investigated by surface plasmon resonance. The N-terminal domain of rLon was shown to interact with the C-terminal, leucine zipper domain of MYC and MAX and to prevent MYC/MAX dimerization. Furthermore, rLon targeted and degraded c-MYC in vitro and in cellular models, through the peptidase domain. In a model of kidney infection, rLon treatment prevented, c-MYC, N-MYC and L-MYC over-expression, MYC-dependent gene expression, specifically renal toxicity genes and pathology, suggesting that rLon recognizes and corrects MYC dysregulation in this disease. The findings describe a multitarget mechanism of MYC inhibition by rLon, and the combined effects achieved by the Lon domains, targeting different MYC epitopes and MYC-dependent functions, with no evidence of toxicity or detrimental effects on homeostatic MYC expression.</p>}},
  author       = {{Ambite, Ines and Wan, Murphy Lam Yim and Tran, Hien Thi and Nazari, Atefeh and Chaudhuri, Arunima and Krintel, Christian and Gomes, Inês and Sabari, Samudra and Ahmadi, Shahram and Carneiro, António N.B.M. and Ishac, Rita and Haq, Farhan and Svanborg, Catharina}},
  issn         = {{2045-2322}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Scientific Reports}},
  title        = {{Multitarget mechanism of MYC inhibition by the bacterial lon protease in disease}},
  url          = {{http://dx.doi.org/10.1038/s41598-025-88093-2}},
  doi          = {{10.1038/s41598-025-88093-2}},
  volume       = {{15}},
  year         = {{2025}},
}