The J anus transcription factor H ap X controls fungal adaptation to both iron starvation and iron excess

Abstract

Balance of physiological levels of iron is essential for every organism. In Aspergillus fumigatus and other fungal pathogens, the transcription factor HapX mediates adaptation to iron limitation and consequently virulence by repressing iron consumption and activating iron uptake. Here, we demonstrate that HapX is also essential for iron resistance via activating vacuolar iron storage. We identified HapX protein domains that are essential for HapX functions during either iron starvation or high-iron conditions. The evolutionary conservation of these domains indicates their wide-spread role in iron sensing. We further demonstrate that a HapX homodimer and the CCAAT-binding complex (CBC) cooperatively bind an evolutionary conserved DNA motif in a target promoter. The latter reveals the mode of discrimination between general CBC and specific HapX/CBC target genes. Collectively, our study uncovers a novel regulatory mechanism mediating both iron resistance and adaptation to iron starvation by the same transcription factor complex with activating and repressing functions depending on ambient iron availability.

The Basic Leucine Zipper Stress Response Regulator Yap5 Senses High-Iron Conditions by Coordination of [2Fe-2S] Clusters

“…These findings suggest that the n-CRD represents a novel structural domain that likely functions as a conserved binding site for Fe/S cluster sensors in fungal stress-responsive regulators. Consistent with this conclusion, a recent study demonstrates that the CGFCX 5 CXC motif in Aspergillus fumigatus HapX is essential for activation of the A. fumigatus CCC1 homolog (41).…”

Deciphering the Combinatorial DNA-binding Code of the CCAAT-binding Complex and the Iron-regulatory Basic Region Leucine Zipper (bZIP) Transcription Factor HapX

“…SreA represses expression of hapX during iron sufficiency and HapX represses sreA during iron starvation (7). Additionally, both SreA and HapX appear to be regulated post-translationally by iron, blocking HapX function and activating SreA function (8).…”

“…Despite the SreA-mediated transcriptional repression of hapX during iron sufficiency, a very recent study surprisingly revealed that HapX is not only crucial for adaptation to iron starvation but also for coping with iron toxicity via activation of cccA, which encodes a vacuolar iron importer (8,9). Strikingly, the latter mode of gene activation not only requires CBC-HapX protein-protein interaction but also cooperative CBC-HapX binding of an evolutionarily conserved bipartite DNA motif within the cccA promoter.…”

Aspergillosis and stem cell transplantation: An overview of experimental pathogenesis studies

“…73 Attenuated virulence has also been reported in other strains of A. fumigatus with mutations in the siderophore synthesis pathway and with other mutations affecting iron metabolism, including HapX, AcuM, and AcuK. 72,[74][75][76] Taken together, these studies strongly suggest that the ability of A. fumigatus to acquire and utilize iron from the host is essential for pathogenicity. This hypothesis is supported by the observation that iron overload within HSCT patients is a risk factor for the development of IA.…”