# CsdA‐LaeB Regulatory Hub Contributes to Aspergillus fumigatus Virulence via Fumiquinazoline C Biosynthesis

## TL;DR

This study finds that a protein interaction in a fungus boosts toxin production, making it more harmful to humans and suggesting new ways to treat fungal infections.

## Contribution

The study identifies a novel RNA-binding protein-based regulatory hub linking secondary metabolism to fungal virulence in Aspergillus fumigatus.

## Key findings

- Disruption of CsdA-LaeB interaction increases fumiquinazoline C production and fungal virulence in mice.
- CsdA and LaeB co-regulate a secondary metabolic gene cluster network, with FqC mediating virulence in vivo.
- Clinical isolates with reduced CsdA/LaeB expression show elevated FqC production, correlating with increased virulence.

## Abstract

Fungal secondary metabolism plays a critical role in pathogen–host interactions, yet the regulatory networks linking metabolic reprogramming to virulence remain poorly understood. This study identifies a conserved regulatory hub in the human pathogen Aspergillus fumigatus, where the RNA‐binding protein (RBP) CsdA interacts with the global regulator LaeB in the nucleus to regulate biosynthesis of the secondary metabolite fumiquinazoline C (FqC). Disruption of the CsdA‐LaeB interaction hyperactivates FqC production, enhancing fungal colonization and lethality in murine invasive aspergillosis models. Integrative metabolomic and transcriptomic analyses reveal that CsdA and LaeB function as co‐regulators of a broader secondary metabolic gene cluster network, with FqC emerging as an effector that mediates virulence in vivo. Genetic validation confirms that FqC is strictly required for the increased virulence phenotype of CsdA‐ or LaeB‐deficient strains, while analyses of clinical isolates demonstrate a striking inverse correlation: reduced CsdA and LaeB expression coincides with elevated FqC production, showing consistency with the infection outcomes of the deletion mutants. This work identifies the RBP‐based interaction that regulates fungal metabolic virulence, shedding new light on the post‐transcriptional regulatory logic linking secondary metabolism to pathogenicity and offering alternative strategies for diagnostic development and therapeutic intervention in invasive fungal diseases.

This study identifies a conserved CsdA‐LaeB hub in Aspergillus fumigatus that regulates secondary metabolite fumiquinazoline C (FqC). Disrupting this hub enhances FqC production and virulence, shedding new light on the post‐transcriptional regulatory logic linking secondary metabolism to pathogenicity and offering alternative strategies for diagnostic development and therapeutic intervention in invasive fungal diseases.