An ensemble-guided approach identifies ClpP as a major regulator of transcript levels in nitric oxide-stressed Escherichia coli

Jonathan L. Robinson, Mark P. Brynildsen

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

The importance of NO{bullet operator} to immunity is highlighted by the diversity of pathogens that require NO{bullet operator}-defensive systems to establish infections. Proteases have been identified to aid pathogens in surviving macrophage attack, inspiring us to investigate their role during NO{bullet operator} stress in Escherichia coli. We discovered that the elimination of ClpP largely impaired NO{bullet operator} detoxification by E. coli. Using a quantitative model of NO{bullet operator} stress, we employed an ensemble-guided approach to identify the underlying mechanism. Iterations of in silico analyses and corresponding experiments identified the defect to result from deficient transcript levels of hmp, which encodes NO{bullet operator} dioxygenase. Interestingly, the defect was not confined to hmp, as δclpP imparted widespread perturbations to the expression of NO{bullet operator}-responsive genes. This work identified a target for anti-infective therapies based on disabling NO{bullet operator} defenses, and demonstrated the utility of model-based approaches for exploring the complex, systems-level stress exerted by NO{bullet operator}.

Original languageEnglish (US)
Pages (from-to)22-34
Number of pages13
JournalMetabolic Engineering
Volume31
DOIs
StatePublished - Sep 1 2015

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology

Keywords

  • ClpP protease
  • Escherichia coli
  • Hmp
  • Kinetic modeling
  • Nitric oxide
  • Nitrosative stress

Fingerprint Dive into the research topics of 'An ensemble-guided approach identifies ClpP as a major regulator of transcript levels in nitric oxide-stressed Escherichia coli'. Together they form a unique fingerprint.

  • Cite this