Ferric reductase-related proteins mediate fungal heme acquisition

Abstract

Heme can serve as iron source in many environments, including the iron-poor animal host environment. The fungal pathobiont Candida albicans expresses a family of extracellular CFEM hemophores that capture heme from host proteins and transfer it across the cell wall to the cell membrane, to be endocytosed and utilized as heme or iron source. Here we identified Frp1 and Frp2, two ferric reductase (FRE)-related proteins that lack an extracellular N-terminal substrate-binding domain, as being required for hemoglobin heme utilization and for sensitivity to toxic heme analogs. Frp1 and Frp2 redistribute to the plasma membrane in the presence of hemin, consistent with a direct role in heme trafficking. Expression of Frp1 with the CFEM hemophore Pga7 can promote heme utilization in Saccharomyces cerevisiae as well, confirming the functional interaction between these proteins. Sequence and structure comparison reveals that the CFEM hemophores are related to the FRE substrate-binding domain that is missing in Frp1/2. We conclude that Frp1/2 and the CFEM hemophores form a functional complex that evolved from ferric reductases to enable extracellular heme uptake.

The flavohemoglobin Yhb1 is a new interacting partner of the heme transporter Str3

“…In S. pombe , the non-iron metalloporphyrin zinc mesoporphyrin (ZnMP) is taken up via two heme uptake pathways that require Shu1 and Str3, respectively (Mourer et al 2015; Normant et al 2018). High concentrations of ZnMP are cytotoxic to yeast cells, presumably due to its interference with essential hemeproteins (Hu et al 2013; Roy et al 2022; Stojiljkovic et al 2001). Building on this observation, we investigated whether ZnMP assimilation could impede Yhb1 function, rendering yeast cells hypersensitive to DETANONOate (a NO donor).…”

“…Non-iron metalloporphyrins (MPPs) are taken up by bacteria and yeasts via heme uptake systems, and they have antibacterial/antifungal activity that is thought to result from interference with essential hemeproteins(Hu et al 2013; Roy et al 2022; Stojiljkovic et al 2001). In the present study, we used the non-iron metalloporphyrin ZnMP instead of hemin.…”

Comprehensive Review on the Virulence Factors and Therapeutic Strategies with the Aid of Artificial Intelligence against Mucormycosis

“…Recently, the presence of two ferric reductase-related proteins, Frp1 and Frp2, which participate in heme utilization, is revealed in C. albicans , akin to the Frp1 and CFEM hemophore complex (comprising Rbt5, Rbt51/Pga10, Pga7) discovered in S. cerevisiae , facilitating extracellular heme uptake for iron. Similar mechanisms, although not confirmed, may be pertinent to Mucorales . Putative haem oxygenase genes in R. arrhizus and L. corymbifera suggest their role in heme breakdown .…”

“…Similar mechanisms, although not confirmed, may be pertinent to Mucorales. 130 Putative haem oxygenase genes in R. arrhizus and L. corymbifera suggest their role in heme breakdown. 100 Hemofungin, an antifungal, disrupts cell walls and inhibits hemoglobin production by targeting HemH/ ferrochelatase, although its higher MIC in Rhizopus raises concerns.…”

Manganese homeostasis modulates fungal virulence and stress tolerance inCandida albicans

“…As transition metal availability is very limited inside the human host, fungal pathogens have evolved sophisticated mechanisms to uptake and utilize these micronutrients at the infection interface. For instance, Fe acquisition by heme utilization and siderophore-mediated uptake are recognized as key virulence factors in many important fungal human pathogens including Candida albicans , Aspergillus fumigatus and Cryptococcus neoformans (Haas, 2012; Bairwa et al, 2017; Fourie et al, 2018; Roy et al, 2022). Similarly, Cu uptake is tightly controlled by the transcription factor Mac1 that is essential for fungal fitness in vivo (Cai et al, 2017; Culbertson et al, 2020; Khemiri et al, 2020).…”