Abstract
Phosphatases, together with kinases and transcription factors, are key components in cellular signalling networks. Here, we present a systematic functional analysis of the phosphatases in Cryptococcus neoformans, a fungal pathogen that causes life-threatening fungal meningoencephalitis. We analyse 230 signature-tagged mutant strains for 114 putative phosphatases under 30 distinct in vitro growth conditions, revealing at least one function for 60 of these proteins. Large-scale virulence and infectivity assays using insect and mouse models indicate roles in pathogenicity for 31 phosphatases involved in various processes such as thermotolerance, melanin and capsule production, stress responses, O-mannosylation, or retromer function. Notably, phosphatases Xpp1, Ssu72, Siw14, and Sit4 promote blood-brain barrier adhesion and crossing by C. neoformans. Together with our previous systematic studies of transcription factors and kinases, our results provide comprehensive insight into the pathobiological signalling circuitry of C. neoformans.
Highlights
Phosphatases, together with kinases and transcription factors, are key components in cellular signalling networks
We retrieved a total of 139 putative phosphatase genes in C. neoformans (Fig. 1a, b and Supplementary Data 1)
Compared to other non-pathogenic and pathogenic yeasts, C. neoformans contains a similar number of putative phosphatases (Fig. 1c and Supplementary Data 3)
Summary
Phosphatases, together with kinases and transcription factors, are key components in cellular signalling networks. The goal of this study was to systematically analyse the functions of the C. neoformans phosphatase network and interplay with its kinase and TF networks to better understand its pathobiological signalling To this end, we constructed a high-quality library of 219 signature-tagged gene-deletion mutant strains representing 109 phosphatases out of 139 putative phosphatases identified in C. neoformans, in addition to 11 signature-tagged mutants representing six phosphatases that we previously constructed[4,5,10,11]. Using a total of 230 signature-tagged mutants representing 114 phosphatases, we analysed their phenotypic traits under 30 distinct in vitro conditions and performed a largescale virulence assay using two model host systems (insect and murine) This entire phosphatase phenome data set is freely available to the public through the C. neoformans Phosphatase Phenome Database (http://phosphatase.cryptococcus.org)
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