Cell detoxification of secondary metabolites by P4-ATPase-mediated vesicle transport.

Abstract

Mechanisms for cellular detoxification of drug compounds are of significant interest in human health. Cyclosporine A (CsA) and tacrolimus (FK506) are widely known antifungal and immunosuppressive microbial natural products. However, both compounds can result in significant side effects when used as immunosuppressants. The insect pathogenic fungus <i>Beauveria bassiana</i> shows resistance to CsA and FK506. However, the mechanisms underlying the resistance have remained unknown. Here, we identify a P4-ATPase gene, <i>BbCRPA</i>, from the fungus, which confers resistance <i>via</i> a unique vesicle mediated transport pathway that targets the compounds into detoxifying vacuoles. Interestingly, the expression of <i>BbCRPA</i> in plants promotes resistance to the phytopathogenic fungus <i>Verticillium dahliae</i> via detoxification of the mycotoxin cinnamyl acetate using a similar pathway. Our data reveal a new function for a subclass of P4-ATPases in cell detoxification. The P4-ATPases conferred cross-species resistance can be exploited for plant disease control and human health protection.