The RNA-binding protein Psc1 functions downstream of the NDR/LATS kinase Cbk1 to modulate CO2 tolerance in Cryptococcus neoformans
4 affiliations
- 1Department of Microbiology, University of Georgia, Athens, Georgia, USA
- 2Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
- 3Department of Molecular Physiology and Biophysics, Carver College of Medicine, The University of Iowa, Iowa City, Iowa, USA
- 4Department of Plant Biology, University of Georgia, Athens, Georgia, USA
Abstract
Cryptococcus neoformans is an opportunistic fungal pathogen responsible for approximately 20% of deaths in patients with HIV/AIDS. Adaptation to host physiological conditions, including high CO2, is required for infection. We discovered that an uncharacterized protein with an RNA-binding domain, Psc1, functions as a basidiomycete-specific suppressor of the kinase mutant cbk1Δ and partially rescues its growth defect in high CO2. Psc1 contains multiple consensus cell wall biosynthesis kinase 1 (Cbk1) phosphorylation sites that are required for maintenance of CO2 fitness. We hypothesized that, in the absence of Cbk1, Psc1 negatively regulates CO2 tolerance by binding to and interfering with the function of mRNAs required for CO2 tolerance. Supporting this model, we found that multiple mRNAs that are required for CO2 tolerance associate with Psc1 in the absence of Cbk1. Furthermore, the transcripts of ZDS3, a gene required for CO2 tolerance, predominantly colocalize with Psc1, which forms condensates in the cbk1Δ mutant at high CO2, correlating with impaired growth. Collectively, our findings support the conclusion that C. neoformans adapts to high CO2 through a post-transcriptional mechanism where Cbk1 phosphorylates Psc1, preventing its binding to, and subsequent functional inhibition of, mRNAs important for CO2 tolerance.
IMPORTANCE: High CO2 is growth-inhibitory, and therefore adaptation to high CO2 stress is a universal cellular phenomenon required for survival. The environmental fungus, Cryptococcus neoformans, encounters high CO2 environments in the host, and thus tolerance to high CO2 is critical for its ability to cause lethal infections. The regulation of Ace2p and morphogenesis (RAM) pathway is required for its growth in high CO2. We found that CO2 tolerance is mediated post-transcriptionally by a downstream target of the RAM pathway, the RNA-binding protein Psc1. In the absence of the RAM pathway, Psc1 sequesters mRNA transcripts required for growth in high CO2, preventing growth. These findings reveal a previously uncharacterized post-transcriptional regulatory mechanism that controls cryptococcal adaptation to high CO2.
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BibTeX
@article{blackburn2026rnabinding,
title = {{The RNA-binding protein Psc1 functions downstream of the NDR/LATS kinase Cbk1 to modulate CO2 tolerance in Cryptococcus neoformans}},
author = {Emma E. Blackburn and Laura C. Ristow and Xiaofeng Xie and Damian J. Krysan and Xiaorong Lin},
journal = {mBio},
year = {2026},
month = sep,
doi = {10.1128/mbio.02051-26},
url = {https://doi.org/10.1128/mbio.02051-26},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The RNA-binding protein Psc1 functions downstream of the NDR/LATS kinase Cbk1 to modulate CO2 tolerance in Cryptococcus neoformans
AU - Emma E. Blackburn
AU - Laura C. Ristow
AU - Xiaofeng Xie
AU - Damian J. Krysan
AU - Xiaorong Lin
PY - 2026
DA - 2026/09/21
JO - mBio
DO - 10.1128/mbio.02051-26
UR - https://doi.org/10.1128/mbio.02051-26
AB - Cryptococcus neoformans is an opportunistic fungal pathogen responsible for approximately 20% of deaths in patients with HIV/AIDS. Adaptation to host physiological conditions, including high CO2, is required for infection. We discovered that an uncharacterized protein with an RNA-binding domain, Psc1, functions as a basidiomycete-specific suppressor of the kinase mutant cbk1Δ and partially rescues its growth defect in high CO2. Psc1 contains multiple consensus cell wall biosynthesis kinase 1 (Cbk1) phosphorylation sites that are required for maintenance of CO2 fitness. We hypothesized that, in the absence of Cbk1, Psc1 negatively regulates CO2 tolerance by binding to and interfering with the function of mRNAs required for CO2 tolerance. Supporting this model, we found that multiple mRNAs that are required for CO2 tolerance associate with Psc1 in the absence of Cbk1. Furthermore, the transcripts of ZDS3, a gene required for CO2 tolerance, predominantly colocalize with Psc1, which forms condensates in the cbk1Δ mutant at high CO2, correlating with impaired growth. Collectively, our findings support the conclusion that C. neoformans adapts to high CO2 through a post-transcriptional mechanism where Cbk1 phosphorylates Psc1, preventing its binding to, and subsequent functional inhibition of, mRNAs important for CO2 tolerance. IMPORTANCE: High CO2 is growth-inhibitory, and therefore adaptation to high CO2 stress is a universal cellular phenomenon required for survival. The environmental fungus, Cryptococcus neoformans, encounters high CO2 environments in the host, and thus tolerance to high CO2 is critical for its ability to cause lethal infections. The regulation of Ace2p and morphogenesis (RAM) pathway is required for its growth in high CO2. We found that CO2 tolerance is mediated post-transcriptionally by a downstream target of the RAM pathway, the RNA-binding protein Psc1. In the absence of the RAM pathway, Psc1 sequesters mRNA transcripts required for growth in high CO2, preventing growth. These findings reveal a previously uncharacterized post-transcriptional regulatory mechanism that controls cryptococcal adaptation to high CO2.
SN - 2150-7511
ER -