Signal-sensing triggers the shutdown of HemKR, regulating heme and iron metabolism in the spirochete Leptospira biflexa.

Juan Andr��s Imelio, Felipe Trajtenberg, Sonia Mondino, Leticia Zarantonelli, Iakov Vitrenko, Laure Lem��e, Thomas Cokelaer, Mathieu Picardeau, Alejandro Buschiazzo
Author Information
  1. Juan Andr��s Imelio: Laboratory of Molecular & Structural Microbiology, Institut Pasteur de Montevideo, Montevideo, Uruguay.
  2. Felipe Trajtenberg: Laboratory of Molecular & Structural Microbiology, Institut Pasteur de Montevideo, Montevideo, Uruguay.
  3. Sonia Mondino: Laboratory of Molecular & Structural Microbiology, Institut Pasteur de Montevideo, Montevideo, Uruguay. ORCID
  4. Leticia Zarantonelli: Unidad Mixta Pasteur INIA, Institut Pasteur de Montevideo, Montevideo, Uruguay.
  5. Iakov Vitrenko: Plateforme Technologique Biomics, C2RT, Institut Pasteur, Universit�� Paris Cit��, Paris, France.
  6. Laure Lem��e: Plateforme Technologique Biomics, C2RT, Institut Pasteur, Universit�� Paris Cit��, Paris, France.
  7. Thomas Cokelaer: Plateforme Technologique Biomics, C2RT, Institut Pasteur, Universit�� Paris Cit��, Paris, France.
  8. Mathieu Picardeau: Biology of Spirochetes Unit, Institut Pasteur, Universit�� Paris Cit��, Paris, France.
  9. Alejandro Buschiazzo: Laboratory of Molecular & Structural Microbiology, Institut Pasteur de Montevideo, Montevideo, Uruguay. ORCID

Abstract

Heme and iron metabolic pathways are highly intertwined, both compounds being essential for key biological processes, yet becoming toxic if overabundant. Their concentrations are exquisitely regulated, including via dedicated two-component systems (TCSs) that sense signals and regulate adaptive responses. HemKR is a TCS present in both saprophytic and pathogenic Leptospira species, involved in the control of Heme metabolism. However, the molecular means by which HemKR is switched on/off in a signal-dependent way, are still unknown. Moreover, a comprehensive list of HemKR-regulated genes, potentially overlapped with iron-responsive targets, is also missing. Using the saprophytic species Leptospira biflexa as a model, we now show that 5-aminolevulinic acid (ALA) triggers the shutdown of the HemKR pathway in live cells, and does so by stimulating the phosphatase activity of HemK towards phosphorylated HemR. Phospho~HemR dephosphorylation leads to differential expression of multiple genes, including of Heme metabolism and transport systems. Besides the Heme-biosynthetic genes hemA and the catabolic hmuO, which we had previously reported as phospho~HemR targets, we now extend the regulon identifying additional genes. Finally, we discover that HemR inactivation brings about an iron-deficit tolerant phenotype, synergistically with iron-responsive signaling systems. Future studies with pathogenic Leptospira will be able to confirm whether such tolerance to iron deprivation is conserved among Leptospira spp., in which case HemKR could play a vital role during infection where available iron is scarce. In sum, HemKR responds to abundance of porphyrin metabolites by shutting down and controlling Heme homeostasis, while also contributing to integrate the regulation of Heme and iron metabolism in the L. biflexa spirochete model.

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MeSH Term

Heme
Leptospira
Iron
Bacterial Proteins
Signal Transduction
Gene Expression Regulation, Bacterial
Aminolevulinic Acid
Phosphorylation

Chemicals

Heme
Iron
Bacterial Proteins
Aminolevulinic Acid

Word Cloud

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