[ SCAN ] Control of heme homeostasis by a link between heme biosynthesis and heme acquisition pathways in Staphylococcus aureus

Title: Control of heme homeostasis by a link between heme biosynthesis and heme acquisition pathways in Staphylococcus aureus

Speaker: Marco Videira

Affiliation: Molecular Mechanisms of Pathogen Resistance, ITQB NOVA

Abstract:

Heme biosynthesis and heme uptake are two pathways distributed among several prokaryotes that allow organisms to obtain heme, which is a key molecule to all living systems. Staphylococcus aureus synthesizes heme de novo through the coproporphyrin-dependent (CPD) pathway, but also captures heme from the host hemoglobin via the Isd heme uptake system. Although both pathways are important for S. aureus survival, how the pathogen controls the intracellular heme content to avoid the toxicity associated with high levels of heme remained an open question. In this work, we show for the first time that the two systems are connected via two key enzymes of the two pathways, namely the heme monoxygenase IsdG of heme uptake system and the coproporphyrin ferrochelatase (CpfC) of the heme biosynthesis pathway. We observed that IsdG has the capacity to impair the ferrochelatase activity of CpfC. This inhibition is linked to a protein-protein interaction that occurs between the IsdG and CpfC proteins, as shown by fluorescence anisotropy and FLIM-FRET. Importantly, it was also observed that the increase of the external heme promotes this interaction. The importance of this crosstalk between the two systems relies on the need to avoid intracellular accumulation of heme which is highly toxic for any bacterial cell. Moreover, a phylogenetical analysis revealed that IsdG-like proteins are present in organisms with heme biosynthetic pathways more often than in organisms that only contain genes for heme uptake systems.

Therefore, we propose that in several bacteria the control of heme homeostasis is done by the heme monoxygenase IsdG.