Figure 1.

Mechanisms of iron acquisition for C. neoformans. The best-characterized mechanism for iron acquisition is the reductive, high affinity uptake pathway that depends on ferric reductase activity, the iron permease Cft1 and the ferroxidase CfO1 [15, 23, 24]. A related iron permease (Cft2) and a ferroxidase (CfO2) are hypothesized to function in vacuolar iron transport but their locations remain to be determined. There are eight ferric or metallo-reductases (Fre1-8) predicted from the genome sequence and reducing activities have also been reported for cell wall melanin (produced by the laccases Lad and Lac2) and the secreted reductant 3-hydroxyanthranilic acid (3-HAA) [15, 70, 71]. At least six siderophore transporters are predicted from the genome although only the Sit1 transporter has been genetically characterized [25]. Existing evidence indicates that C. neoformans does not produce its own siderophores [72]. A heme uptake system involves the mannoprotein Cig1, which may be a hemophore, and trafficking functions that include the ESCRT protein Vps23 [26, 35]. This pathway is hypothesized to deliver heme to the vacuole via a pathway that may include the homotypic fusion and vacuole protein sorting (HOPS) complex [73, 74].