Multifactor transcriptional control of alternative oxidase induction integrates diverse environmental inputs to enable fungal virulence

Zhongle Liu, Pauline Basso, Saif Hossain, Sean D. Liston, Nicole Robbins, Luke Whitesell, Suzanne M. Noble () and Leah E. Cowen ()
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Zhongle Liu: University of Toronto
Pauline Basso: UCSF Department of Microbiology & Immunology
Saif Hossain: University of Toronto
Sean D. Liston: University of Toronto
Nicole Robbins: University of Toronto
Luke Whitesell: University of Toronto
Suzanne M. Noble: UCSF Department of Microbiology & Immunology
Leah E. Cowen: University of Toronto

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Metabolic flexibility enables fungi to invade challenging host environments. In Candida albicans, a common cause of life-threatening infections in humans, an important contributor to flexibility is alternative oxidase (Aox) activity. Dramatic induction of this activity occurs under respiratory-stress conditions, which impair the classical electron transport chain (ETC). Here, we show that deletion of the inducible AOX2 gene cripples C. albicans virulence in mice by increasing immune recognition. To investigate further, we examined transcriptional regulation of AOX2 in molecular detail under host-relevant, ETC-inhibitory conditions. We found that multiple transcription factors, including Rtg1/Rtg3, Cwt1/Zcf11, and Zcf2, bind and regulate the AOX2 promoter, conferring thousand-fold levels of inducibility to AOX2 in response to distinct environmental stressors. Further dissection of this complex promoter revealed how integration of stimuli ranging from reactive species of oxygen, nitrogen, and sulfur to reduced copper availability is achieved at the transcriptional level to regulate AOX2 induction and enable pathogenesis.

Date: 2023
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DOI: 10.1038/s41467-023-40209-w

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