Abstract

Many microbial symbionts form distinct partnerships with different hosts. While the mechanisms specific to each partnership are well understood, the shared strategies that a symbiont uses to interact with disparate hosts remain understudied. Here, we report that the endophytic and entomopathogenic fungus Metarhizium robertsii deploys the farnesyltransferase inhibitor barceloneic acid A (BA-A) to modulate the physiology of insects and plants to develop parasitism and mutualism, respectively. During insect infection, BA-A inhibits host Ras protein farnesylation, reducing its cell membrane localization and suppressing MAPK/ERK phosphorylation and production of the hormone 20-hydroxyecdysone. This suppresses larval pupation and decelerates larval death by upregulating antibacterial peptides to kill gut-derived opportunistic pathogens in the hemocoel, prolonging M. robertsii ’s access to nutrient-rich larval hemolymph for maximal reproduction. BA-A also inhibits the plant farnesyltransferase, downregulating the defense-related protein PR2 to facilitate mutualism development. The BA-A biosynthetic gene cluster was characterized, which is activated during interactions with insects and plants.