Bacterial cell cycle control by citrate synthase independent of enzymatic activity

Abstract
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Abstract

Proliferating cells must coordinate central metabolism with the cell cycle. How central energy metabolism regulates bacterial cell cycle functions is not well understood. Our forward genetic selection unearthed the Krebs cycle enzyme citrate synthase (CitA) as a checkpoint regulator controlling the G1→S transition in the polarized alpha-proteobacterium Caulobacter crescentus, a model for cell cycle regulation and asymmetric cell division. We find that loss of CitA promotes the accumulation of active CtrA, an essential cell cycle transcriptional regulator that maintains cells in G1-phase, provided that the (p)ppGpp alarmone is present. The enzymatic activity of CitA is dispensable for CtrA control and functional citrate synthase paralogs cannot replace CitA in promoting S-phase entry. Our evidence suggests that CitA was appropriated specifically to function as a moonlighting enzyme to link central energy metabolism with S-phase entry. Control of the G1-phase with a central metabolic enzyme may be a common mechanism of cellular regulation.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Tn-seq and metabolomics data.

The following data sets were generated

(2020) Polymerase occupancy (ChIP-Seq) in WT and mutants of Caulobacter crescentus NA1000
NCBI Gene Expression Omnibus, GSE144533.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE144533

The following previously published data sets were used

1. Fumeaux C
2. Radhakrishnan SK
3. Ardissone S
4. Théraulaz L
5. Frandi A
6. Martins D
7. Nesper J
8. Abel S
9. Jenal U
10. Viollier PH
(2014) Examination of 5 transcripton factor binding in two different species
NCBI Gene Expression Omnibus, GSE52849.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE52849

Article and author information

Author details

Matthieu Bergé

Department Microbiology and Molecular Medicine, Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva, Switzerland

For correspondence
matthieu.berge@unige.ch

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-0910-6114
Julian Pezzatti

Institute of Pharmaceutical Sciences of Western Switzerland (ISPSO), University of Geneva, Geneva, Switzerland

Competing interests
The authors declare that no competing interests exist.
Víctor González-Ruiz

Institute of Pharmaceutical Sciences of Western Switzerland (ISPSO), University of Geneva, Geneva, Switzerland

Competing interests
The authors declare that no competing interests exist.
Laurence Degeorges

Department Microbiology and Molecular Medicine, Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva, Switzerland

Competing interests
The authors declare that no competing interests exist.
Geneviève Mottet-Osman

Department Microbiology and Molecular Medicine, Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva, Switzerland

Competing interests
The authors declare that no competing interests exist.
Serge Rudaz

Institute of Pharmaceutical Sciences of Western Switzerland (ISPSO), University of Geneva, Geneva, Switzerland

Competing interests
The authors declare that no competing interests exist.
Patrick H Viollier

Department Microbiology and Molecular Medicine, Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva, Switzerland

For correspondence
patrick.viollier@unige.ch

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5249-9910

Funding

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (31003A_182576)

Patrick H Viollier

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.