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Genome-wide functional analysis of phosphatases in the pathogenic fungus Cryptococcus neoformans
Jae-Hyung Jin1, Kyung-Tae Lee1, Joohyeon Hong1
1Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Korea.
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.
Insights
This study systematically analyzed phosphatases in the fungal pathogen Cryptococcus neoformans, identifying key roles in virulence and pathogenicity. Several phosphatases were found to be crucial for crossing the blood-brain barrier, impacting fungal meningoencephalitis.
Area of Science:
- Molecular Biology
- Mycology
- Pathogen Biology
Background:
- Phosphatases are critical regulators of cellular signaling pathways, alongside kinases and transcription factors.
- Cryptococcus neoformans is a significant fungal pathogen responsible for life-threatening meningoencephalitis.
Purpose of the Study:
- To systematically analyze the functions of phosphatases in Cryptococcus neoformans.
- To identify phosphatases involved in fungal virulence and pathogenicity.
Main Methods:
- Systematic functional analysis of 114 putative phosphatases using 230 signature-tagged mutant strains.
- In vitro growth assays under 30 distinct conditions.
- Large-scale virulence and infectivity assays in insect and mouse models.
Main Results:
- At least one function was identified for 60 of the analyzed phosphatases.
- 31 phosphatases were found to play roles in pathogenicity, including thermotolerance, melanin and capsule production, stress responses, O-mannosylation, and retromer function.
- Specific phosphatases (Xpp1, Ssu72, Siw14, Sit4) were identified to promote blood-brain barrier adhesion and crossing.
Conclusions:
- This study provides comprehensive insights into the signaling circuitry of Cryptococcus neoformans.
- The identified phosphatases are crucial for fungal virulence and represent potential therapeutic targets for cryptococcal infections.
