Abstract
Pathogenic microorganisms employ specialized virulence factors to cause disease. Biofilm formation and the production of a polysaccharide capsule are two important virulence factors in Cryptococcus neoformans, the fungal pathogen that causes meningoencephalitis. Here, we show that the bipolar disorder drug lithium inhibits formation of both virulence factors by a mechanism involving dysregulation of the ubiquitin/proteasome system. By using a chemical genetics approach and bioinformatic analyses, we describe the cellular landscape affected by lithium treatment. We demonstrate that lithium affects many different pathways in C. neoformans, including the cAMP/protein kinase A, inositol biosynthesis, and ubiquitin/proteasome pathways. By analyzing mutants with defects in the ubiquitin/proteasome system, we uncover a role for proteostasis in both capsule and biofilm formation. Moreover, we demonstrate an additive influence of lithium and the proteasome inhibitor bortezomib in inhibiting capsule production, thus establishing a link between lithium activity and the proteasome system. Finally, we show that the lithium-mimetic drug ebselen potently blocks capsule and biofilm formation, and has additive activity with lithium or bortezomib. In summary, our results illuminate the impact of lithium on C. neoformans, and link dysregulation of the proteasome to capsule and biofilm inhibition in this important fungal pathogen.