Nuclear BbAtg8 interacts with BbMac1 as a transcriptional modulator to sustain nuclear copper homeostasis during...

Pathogenic fungi endure host impose copper starvation by tightly coordinating trace metal homeostasis. However, how pathogens synchronize endogenous metal recycling with exogenous copper uptake to promote infection remains enigmatic. Using the entomopathogenic fungus Beauveria bassiana, we uncovered a synergistic regulatory network that prioritizes nuclear copper enrichment during conidial germination. Under copper deprivation, the fungus deploys a highly coordinated dual-track survival strategy. In the cytoplasm, the core autophagy protein BbAtg8 drives autophagic flux, specifically triggering mitophagy to degrade mitochondria, thereby promoting the turnover and mobilization of endogenous copper stores. Concurrently, a nonlipidated pool of BbAtg8 translocates to the nucleus to coordinate exogenous uptake. Within the nucleus, BbAtg8 directly interacts with the copper-fist transcription factor BbMac1 via a functional Atg8-interacting motif (AIM). This physical interaction serves as a potent transcriptional modulator, significantly enhancing BbMac1's DNA-binding affinity. Consequently, the Atg8-Mac1 complex hyper-activates the expression of three functionally redundant copper transporters (BbCtr1, BbCtr2, and BbCtr4) to aggressively absorb extracellular copper. Strikingly, severe copper deprivation triggers a dynamic spatial enrichment of these classical copper transporters at the nuclear envelope, which correlates with the sustained maintenance of nuclear copper homeostasis required for essential genomic functions and full fungal virulence. Together, these findings reveal how pathogens synchronize mitophagy-mediated endogenous turnover with Mac1-driven exogenous uptake, fundamentally expanding the role of autophagy proteins BbAtg8 into direct transcriptional coordinators of metal homeostasis. This dual-track regulatory model not only deepens our understanding of fungal adaptation to nutritional immunity but also provides potential targets for disrupting copper homeostasis to control fungal pathogens.