A chemical genetic screen reveals a role for proteostasis in capsule and biofilm formation by Cryptococcus neoformans

Authors:

François L. Mayer1, Eddy Sánchez-León1, James W. Kronstad1

doi: 10.15698/mic2018.11.656
Volume 5, pp. 495 to 510, published 31/10/2018.

PDF Download PubMed Link Supplemental Information
Affiliations:

1 Michael Smith Laboratories, Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada.

Keywords: 

Cryptococcus neoformans, lithium, proteostasis, capsule, biofilm

Corresponding Author(s):

James W. Kronstad, Michael Smith Laboratories, The University of British Columbia, 301-2185 East Mall, Vancouver, BC, Canada, V6T 1Z4; Tel: (+1) 604 822 4732; Fax: (+1) 604 822 2114; kronstad@msl.ubc.ca

Conflict of interest statement:

The authors declare that they have no conflicts of interest.

Please cite this article as:

François L. Mayer, Eddy Sánchez-León, James W. Kronstad (2018). A chemical genetic screen reveals a role for proteostasis in capsule and biofilm formation by Cryptococcus neoformans. Microbial Cell: in press.

© 2018 Mayer et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.

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.