A widespread family of ribosomal peptide metallophores involved in bacterial adaptation to metal stress
Ribosomally synthesized and posttranslationally modified peptides (RiPPs) are a structurally diverse group of natural products that bacteria employ in their survival strategies. Herein, we characterized the structure, the biosynthetic pathway, and the mode of action of a RiPP family called bufferins. With thousands of homologous biosynthetic gene clusters throughout the bacterial phylogenetic tree, bufferins form by far the largest family of RiPPs modified by multinuclear nonheme iron-dependent oxidases (MNIO, DUF692 family). Using <i>Caulobacter vibrioides</i> bufferins as a model, we showed that the conserved Cys residues of their precursors are transformed into 5-thiooxazoles, further expanding the reaction range of MNIO enzymes. This rare modification is installed in conjunction with a partner protein of the DUF2063 family. Bufferin precursors are rare examples of bacterial RiPPs found to feature an N-terminal Sec signal peptide allowing them to be exported by the ubiquitous Sec pathway. We reveal that bufferins are involved in copper homeostasis, and their metal-binding propensity requires the thiooxazole heterocycles. Bufferins enhance bacterial growth under copper stress by complexing excess metal ions. Our study thus describes a large family of RiPP metallophores and unveils a widespread but overlooked metal homeostasis mechanism in bacteria.
Authors
- Gabriel Billon (ORCID: https://orcid.org/0000-0002-4693-5106)
- Françoise Jacob‐Dubuisson (ORCID: https://orcid.org/0000-0002-5102-1704)
- Guy Lippens (ORCID: https://orcid.org/0000-0002-8236-0901)
- Enrico Falcone (ORCID: https://orcid.org/0000-0002-1944-3552)
- Svetlana Dubiley (ORCID: https://orcid.org/0000-0001-9225-5534)
- Francesco Stellato (ORCID: https://orcid.org/0000-0001-8102-7982)
- Giuseppe Sicoli (ORCID: https://orcid.org/0000-0003-4872-5660)
- Emiliano De Santis (ORCID: https://orcid.org/0000-0001-5029-7429)
- Céline Henry (ORCID: https://orcid.org/0000-0002-2355-1791)
- Rudy Antoine (ORCID: https://orcid.org/0000-0002-7369-0626)
- Séverine Zirah (ORCID: https://orcid.org/0000-0001-6082-8414)
- Lydie Oliveira Correia (ORCID: https://orcid.org/0000-0002-8590-250X)
- Alex Rivera-Millot (ORCID: https://orcid.org/0000-0001-8431-5509)
- Laura Leprévost
- Céline Guillaume
- Yanyan Li (ORCID: https://orcid.org/0000-0002-3156-391X)
- Sophie Jünger
Institutions
- University of Rome Tor Vergata (IT)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Istituto Nazionale di Fisica Nucleare (IT)
- Institut National des Sciences Appliquées de Toulouse (FR)
- AgroParisTech (FR)
- Université de Lille (FR)
- Université Paris-Saclay (FR)
- Institut Pasteur de Lille (FR)
- Microbiologie de l’alimentation au service de la santé (FR)
- Centre Hospitalier Universitaire de Lille (FR)
- Institut National de la Recherche Agronomique du Niger (NE)
- Center for Infection and Immunity of Lille (FR)
- Bausch Health (Canada) (CA)
- Laboratoire de Chimie de Coordination (FR)
- Molécules de Communication et Adaptation des Micro-organismes (FR)
- Laboratoire de Réactivité de Surface (FR)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2024-11-27
- DOI
- https://doi.org/10.1073/pnas.2408304121
- Citations
- 24
- Primary Topic
- Bacterial Genetics and Biotechnology
- Type
- article
- Field-Weighted Citation Impact
- 13.21
Funders
- Agence Nationale de la Recherche
- European Synchrotron Radiation Facility
- Muséum National d'Histoire Naturelle
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement