Cell death induction in Aspergillus fumigatus: accentuating drug toxicity through inhibition of the unfolded protein response (UPR)

Abstract

One of the most potent opportunistic fungal pathogens of humans is Aspergillus fumigatus, an environmental mold that causes a life-threatening pneumonia with a high rate of morbidity and mortality. Despite advances in therapy, issues of drug toxicity and antifungal resistance remain an obstacle to effective therapy. This underscores the need for more information on fungal pathways that could be pharmacologically manipulated to either reduce the viability of the fungus during infection, or to unleash the fungicidal potential of current antifungal drugs. In this review, we summarize the emerging evidence that the ability of A. fumigatus to sustain viability during stress relies heavily on an adaptive signaling pathway known as the unfolded protein response (UPR), thereby exposing a vulnerability in this fungus that has strong potential for future therapeutic intervention.

Keywords: Aspergillus fumigatus; ER stress; HacA; IreA; UPR; cell death.

Graphical abstract

Fig. 1

UPR signaling in mammals and fungi. Top: The mammalian UPR comprises three ER-transmembrane sensors that are activated by the accumulation of unfolded proteins in the ER lumen: IRE1, PERK and ATF6. The IRE1 protein has a cytosolic region containing both kinase (K) and RNase (R) domains. Upon activation, the RNase cleaves an intron (shown in red) from the XBP1u (unspliced) mRNA. The resulting XBP1s (spliced) mRNA contains a translational frame-shift that directs the synthesis of the XBP1 transcription factor required for UPR target gene induction in the nucleus. The PERK sensor contains a cytosolic kinase domain which, when activated, phosphorylates eIF2α (eukaryotic initiation factor 2 alpha), resulting in a global attenuation of protein synthesis that serves to reduce further influx of client proteins into the ER. However, the mRNA encoding the ATF4 transcription factor is able to bypass this translational block, allowing it to contribute to the transcriptional rewiring necessary to restore ER homeostasis. The ATF6 sensor has a cytosolic transcription factor domain (ATF6p50). Upon activation, the protein moves to the Golgi apparatus, where the ATF6p50 transcription factor is released from the sensor by the activity of site-1 protease (S1p) and site-2 protease (S2p). Bottom: The UPR pathway in A. fumigatus. Unfolded proteins activate the IreA RNase to cleave an intron from the hacA^u mRNA, creating a frame-shift in the resulting hacAⁱ mRNA that translates the HacA transcription factor (the canonical pathway). Both canonical and non-canonical functions for IreA contribute to the expression of virulence-related traits, which jointly support both pathogenicity during infection and resistance to antifungal drugs.