Ferric reductase-related proteins mediate fungal heme acquisition

Area of Science:

• Microbiology
• Mycology
• Biochemistry

Background:

• Heme is a vital iron source, particularly in iron-limited host environments.
• Fungal pathobionts like Candida albicans utilize host heme for survival and virulence.
• Extracellular CFEM hemophores in C. albicans capture and transport host heme.

Purpose of the Study:

• To identify and characterize novel proteins involved in heme utilization by Candida albicans.
• To elucidate the functional interaction between ferric reductase (FRE)-related proteins and CFEM hemophores in heme uptake.
• To understand the evolutionary origins of extracellular heme uptake mechanisms.

Main Methods:

• Identification of ferric reductase (FRE)-related proteins Frp1 and Frp2.
• Analysis of Frp1 and Frp2 function in hemoglobin heme utilization and sensitivity to heme analogs.
• Subcellular localization studies of Frp1 and Frp2 in the presence of hemin.
• Functional complementation experiments in Saccharomyces cerevisiae.

Main Results:

• Frp1 and Frp2 are essential for utilizing hemoglobin heme and tolerating toxic heme analogs.
• Frp1 and Frp2 localize to the plasma membrane upon hemin exposure, indicating a role in heme trafficking.
• Co-expression of Frp1 and the CFEM hemophore Pga7 enables heme utilization in Saccharomyces cerevisiae.
• CFEM hemophores share structural similarities with the substrate-binding domain of FREs.

Conclusions:

• Frp1 and Frp2, along with CFEM hemophores, form a functional complex for extracellular heme uptake.
• This complex likely evolved from FREs to facilitate heme acquisition in host environments.
• The findings provide insights into fungal iron metabolism and host-pathogen interactions.