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Moonlighting proteins activate transformation in epigenetically-differentiated phase variants of multidrug-resistant Streptococcus pneumoniae

View ORCID ProfileMin Jung Kwun, View ORCID ProfileAlexandru V. Ion, View ORCID ProfileMarco R. Oggioni, View ORCID ProfileStephen D. Bentley, View ORCID ProfileNicholas J. Croucher
doi: https://doi.org/10.1101/2022.03.07.483185
Min Jung Kwun
1MRC Centre for Global Infectious Disease Analysis, Sir Michael Uren Hub, White City Campus, Imperial College London, London, W12 0BZ, UK
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Alexandru V. Ion
1MRC Centre for Global Infectious Disease Analysis, Sir Michael Uren Hub, White City Campus, Imperial College London, London, W12 0BZ, UK
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Marco R. Oggioni
2Department of Genetics, University of Leicester, University Road, Leicester, LE1 7RH
3Dipartimento di Farmacia e Biotecnologie, Università di Bologna, Via Irnerio 42, 40126 Bologna, Italy
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Stephen D. Bentley
4Parasites & Microbes, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK
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Nicholas J. Croucher
1MRC Centre for Global Infectious Disease Analysis, Sir Michael Uren Hub, White City Campus, Imperial College London, London, W12 0BZ, UK
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  • For correspondence: n.croucher@imperial.ac.uk
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Abstract

Transformation of Streptococcus pneumoniae GPSC1 has enabled vaccine evasion and the acquisition of antibiotic resistance. Epigenetic phase variants of GPSC1 isolate RMV7, differentiated by rearrangements at the tvr restriction-modification locus, differed ∼100-fold in their transformation efficiency. This variation was recapitulated in knock-in mutants of the relevant tvr alleles. RNA-seq showed the difference was due to blocking of the early competence regulatory cascade. The more transformable variant upregulated expression of manLMN, encoding a carbon source importer. This was shown to be necessary for efficient competence induction, despite being dispensable for growth in rich media. Transformation was promoted by import of N-acetylglucosamine, which activated competence through an orthologue of the gram-negative competence regulator TfoX, and an enzyme likely involved in nucleotide-mediated signalling. A mobile genetic element was more active in the less transformable variant, which limited competence induction through inhibiting CIRCE motif binding by the chaperone regulator HrcA. Correspondingly, both heat shock and decreased Ca2+ concentrations reduced competence by limiting HrcA binding regulatory sequence motifs. Hence both ManLMN and HrcA moonlighted as activators of competence. Such proteins may be important in potentiating horizontal DNA exchange, as selection on their primary function likely constrains them from mutating into alleles that selfishly downregulate transformation.

Competing Interest Statement

NJC has received an investigator-initiated award from GlaxoSmithKline and consulted for Pfizer.

Footnotes

  • Added detail in the Methods section.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted April 04, 2022.
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Moonlighting proteins activate transformation in epigenetically-differentiated phase variants of multidrug-resistant Streptococcus pneumoniae
Min Jung Kwun, Alexandru V. Ion, Marco R. Oggioni, Stephen D. Bentley, Nicholas J. Croucher
bioRxiv 2022.03.07.483185; doi: https://doi.org/10.1101/2022.03.07.483185
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Moonlighting proteins activate transformation in epigenetically-differentiated phase variants of multidrug-resistant Streptococcus pneumoniae
Min Jung Kwun, Alexandru V. Ion, Marco R. Oggioni, Stephen D. Bentley, Nicholas J. Croucher
bioRxiv 2022.03.07.483185; doi: https://doi.org/10.1101/2022.03.07.483185

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