Molecular Mechanisms of Hypoxic Responses via Unique Roles of Ras1, Cdc24 and Ptp3 in a Human Fungal Pathogen


When Cryptococcus neoformans, an environmental fungal pathogen, enters the human host, it encounters a low oxygen condition. The well conserved Ras1 and Cdc24 proteins are known for their key roles in maintenance of the actin cytoskeletal integrity in eukaryotic cells. In this work, we show a unique role of RAS1 and CDC24 in the growth of C. neoformans in a low oxygen environment. Actin polarization, however, appeared normal in the ras1Δ and cdc24Δ strains under hypoxic conditions for up to eight hours. We show that PTP3 is required for hypoxic growth and it can rescue the hypoxic growth defect in ras1Δ and cdc24Δ. Genetic analysis suggested that RAS1 and CDC24 function linearly while CDC24 and PTP3 function parallelly in regulating hypoxic growth. RNA sequencing combined with analysis by small molecular inhibitors revealed that RAS1, CDC24 and PTP3 regulate several biological processes such as ergosterol biosynthesis, chromosome organization, RNA processing and protein translation which are required in the cryptococcal response to hypoxic conditions.


Vyšlo v časopise: Molecular Mechanisms of Hypoxic Responses via Unique Roles of Ras1, Cdc24 and Ptp3 in a Human Fungal Pathogen. PLoS Genet 10(4): e32767. doi:10.1371/journal.pgen.1004292
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pgen.1004292

Souhrn

When Cryptococcus neoformans, an environmental fungal pathogen, enters the human host, it encounters a low oxygen condition. The well conserved Ras1 and Cdc24 proteins are known for their key roles in maintenance of the actin cytoskeletal integrity in eukaryotic cells. In this work, we show a unique role of RAS1 and CDC24 in the growth of C. neoformans in a low oxygen environment. Actin polarization, however, appeared normal in the ras1Δ and cdc24Δ strains under hypoxic conditions for up to eight hours. We show that PTP3 is required for hypoxic growth and it can rescue the hypoxic growth defect in ras1Δ and cdc24Δ. Genetic analysis suggested that RAS1 and CDC24 function linearly while CDC24 and PTP3 function parallelly in regulating hypoxic growth. RNA sequencing combined with analysis by small molecular inhibitors revealed that RAS1, CDC24 and PTP3 regulate several biological processes such as ergosterol biosynthesis, chromosome organization, RNA processing and protein translation which are required in the cryptococcal response to hypoxic conditions.


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