AnBir1: a conserved fungal inhibitor of apoptosis regulates caspase activity and core processes in Aspergillus nidulans

Regulated cell death (RCD) is a highly conserved and coordinated cellular demise process. In animals, the fate of cells depends on the precise regulation of RCD, with inhibitors of apoptosis proteins (IAPs) playing a major role as negative regulators of cellular death. In fungi, RCD regulates crucial processes, including growth, development, stress response, host-pathogen interactions and more. However, the biochemical details of this process are not well understood in this kingdom. IAPs are, remarkably, one of the few RCD/Apoptosis-regulatory proteins that are conserved in fungi. Here, we performed large-scale bioinformatic analyses of IAPs in sequenced fungal genomes. While most fungal organisms have a single IAP gene (81.65 % of the genomes analyzed here), some fungi lack IAPs altogether and others have multiple IAP-like genes. Using the Aspergillus nidulans IAP, AnBir1, we show that this protein is required for survival and regulates cell death by inhibiting caspase-like activity. Moreover, disrupting RCD by constitutively expressing AnBir1 impacted fundamental processes, including development, stress response and secondary metabolism. We also show that fungal RCD can be hijacked for therapeutic purposes. Using virus-induced gene silencing (VIGS), we targeted the AnBir1 homolog of the plant pathogenic fungus Sclerotinia sclerotiorum (SsBir1) during plant infection. Targeting SsBir1 resulted in enhanced resistance to S. sclerotiorum infection. We propose that IAPs play a critical role in regulating caspase activities and other RCD-related processes in fungi and may constitute a novel therapeutic target for fungal infections.