From energy sensing to epigenetic activation: The AMPK/TrSnf1-ACE3-MST2 pathway orchestrates cellulase synthesis in...

Fungal gene expression often relies on energy-sensing kinase Snf1 and histone acetyltransferase, particularly for highly expressed or rapidly modulated genes such as those encoding cellulases. Cellulase production by Trichoderma reesei is of great industrial importance; however, most studies on Snf1 function have focused on yeast. This study aimed to determine the mechanisms underlying the rapid response of the Snf1 ortholog in T. reesei (TrSnf1) to carbon source depletion and the subsequent activation of cellulase gene transcription. TrSnf1 senses glucose depletion relieves carbon catabolite repression (CCR) and ultimately triggers cellulase gene expression. Multi-omics analysis identified the histone acetyltransferase MST2 and highlighted the regulatory role of its interaction with TrSnf1 in cellulase expression. MST2 deletion impairs cellulase gene expression, suggesting that its interaction with MST2 is critical for its regulatory function. MST2 is involved in histone H3 acetylation and RNA polymerase binding to cellulase gene promoters. We propose that the TrSnf1-MST2-ACE3 regulatory pathway orchestrates the transcriptional activation of cellulase. This study addresses a critical gap in the CCR regulatory network of T. reesei, specifically the persistent CCR observed in CRE1-knockout strains. Our study uncovered a novel CRE1-independent CCR signaling pathway and provides a theoretical foundation for developing high-yield cellulase strains through genetic engineering.