Regulatory functions of AcuK and AcuM transcription factors in fungal metabolic adaptation, stress response, and virulence

Fungal species thrive in diverse ecological niches and must dynamically adjust their metabolism, growth, and development in response to environmental fluctuations. Transcriptional regulation plays a pivotal role in these adaptive processes, with Zn₂Cys₆ transcription factors constituting the largest family of fungal-specific regulators that orchestrate metabolism, development, and pathogenicity. Among these, AcuK and AcuM represent a distinct subfamily with diverse key regulatory functions. In this review, we provide a comprehensive analysis of AcuK and AcuM functions across various fungal species, including major human pathogens (<i>Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans, Talaromyces marneffei</i>) and model saprophytic fungi (<i>Aspergillus nidulans, Neurospora crassa, Podospora anserina, Saccharomyces cerevisiae</i>). Our analysis reveals that AcuK and AcuM regulate core metabolic pathways, particularly alternative carbon utilization via gluconeogenesis (e.g., <i>acuG</i> encoding fructose-1,6-bisphosphatase and <i>acuF</i> encoding phosphoenolpyruvate carboxykinase) and alternative respiration (e.g., <i>aox</i> encoding alternative oxidase). Beyond metabolic regulation, AcuK and AcuM play crucial roles in a host-induced stress adaptation, especially responses to iron limitation, hypoxia, and host immune interactions-factors that are critical for fungal pathogenicity. Additionally, these transcription factors influence nitric oxide detoxification by modulating <i>YHB1</i>, a heme- and oxygen-dependent nitric oxide dioxygenase. Structural modelling of AcuK/AcuM heterodimer formation and DNA-binding interactions provides mechanistic insights into their regulatory functions. Understanding these transcriptional networks not only advances our knowledge of fungal adaptation but also highlights AcuK and AcuM as potential targets for antifungal therapy.