Dataset Information

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

ABSTRACT: In this study, we discovered that elimination of ClpP in E. coli largely impaired its ability to detoxify nitric oxide (NO•). Using a quantitative model of NO• stress, we employed an ensemble approach to identify the underlying mechanism. The ensemble of models consisted of 127 plausible mechanisms through which ΔclpP could impact the NO• response network, and in silico analyses identified conditions enabling discrimination between mechanisms. The corresponding experiments were conducted and used to reject inconsistent mechanisms until the attenuated NO• detoxification of ΔclpP was attributed to deficient transcript levels of hmp, which encodes NO• dioxygenase. Further analysis (including RNA sequencing) revealed that ΔclpP imparted widespread perturbations to the expression of NO•-responsive genes. This work identified a target for anti-infective therapies based on disabling NO• defenses, and demonstrated the utility of model-based approaches for exploring the complex, systems-level stress exerted by NO•.

ORGANISM(S): Escherichia coli str. K-12 substr. MG1655

PROVIDER: GSE60522 | GEO | 2015/08/18

SECONDARY ACCESSION(S): PRJNA258462

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:The peptidase ClpP is conserved from bacteria to human. In the mitochondrial matrix, it multimerizes and forms a macromolecular proteasome-like cylinder. Because of its known relevance for the mitochondrial unfolded protein response during cell stress, we characterized two ClpP knock-out mouse founder lines and documented similar phenotypes. Ubiquitously, ClpP absence led to accumulation of its interactor protein ClpX without transcript upregulation. Interestingly, most wild-type tissues with substantial ClpP amounts had no detectable ClpX. This inverse correlation suggests that ClpX levels and degradation are regulated by ClpP. The expectation of similar protein levels, in view of a reported association of heptameric ClpP rings with hexameric ClpX rings, was confirmed only in testis of wild-type animals. Germline tissue was exceptional also in its vulnerability to ClpP deletion, with both founder lines showing complete infertility for males and females. Otherwise, ubiquitous mitochondrial dysfunction was apparent from severe growth retardation and reduced spontaneous motor activity of the animals, and from a pronounced decrease in pre-/postnatal survival. Spermatogenesis was found aborted at the spermatid stage, acrosomes and axonemes were not formed. Overall, tissue-specific roles of ClpP were evident by this massive effect for germ cells, mild bioenergetic deficits in muscle and liver tissues, and excellent compensation in brain. ClpX was previously reported to chaperone unfolded proteins and also DNA condensation in mitochondria, so it is likely that this pathway is particularly susceptible in germ cells. In conclusion, our study indicates that the role of ClpP in quality control is indispensable during development for cells with rapid changes of mitochondrial numbers, and is relevant during aging for growth and survival of the organism. Factorial design comparing ClpP knock-out mice with wild type littermates in five different tissues (brain, testis, liver, skeletal and heart muscle)

Dataset Information

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

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets