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Peer-reviewedCC BYPLOS Biology

An inositol receptor Itr4 coordinates carbon catabolite regulation and virulence in Cryptococcus neoformans

  • Yina Wang1,2
  • Robert J Tancer1,2
  • Maggie Wear3
  • Katrina M Jackson4
  • Yu Zhang1,2
  • Kan Li5
  • Jun Wang5
  • Yong-Gui Gao6
  • Kirsten Nielsen7
  • Arturo Casadevall3
  • Chaoyang Xue1,2
7 affiliations
  1. 1Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, New Jersey, United States of America.
  2. 2Department of Microbiology, Biochemistry and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, New Jersey, United States of America.
  3. 3Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Medicine, Baltimore, Maryland, United States of America.
  4. 4Pathogen and Microbiome Institute, Northern Arizona University, Flagstaff, Arizona, United States of America.
  5. 5Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey, United States of America.
  6. 6School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
  7. 7Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, Blacksburg, Virginia, United States of America.
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Abstract

Nutrient sensing and utilization are critical for microbes to adapt to their environment and evade predators. The encapsuled yeast Cryptococcus neoformans has a unique ability to sense and utilize the sugar inositol as both a signaling molecule and as a carbon source. This trait is advantageous not only in the natural environment but also to promote its pathogenesis, including invasion of the central nervous system. In this study, we have identified a novel inositol transporter-like receptor (transceptor) Itr4 that coordinates inositol and glucose metabolism by regulating inositol transporters (ITRs) and glucose sensor Hxs1. Itr4 binds inositol and regulates the function of other ITRs and its loss leads to a significant decrease in inositol uptake activity, resulting in a lack of mating, reduced capsule size, reduced blood–brain barrier (BBB) penetration, and virulence attenuation. Mutagenesis analysis of Itr4 protein identified an essential N-terminal tail and two amino acids, Q388 and Q389, as sites of functional importance. The ITR4Q388A, Q389A allele showed a dominant phenotype with increased inositol uptake, enlarged capsule and significantly attenuated virulence. In summary, we identify a new C. neoformans inositol transceptor, Itr4, the first such example in eukaryotes, with novel regulatory roles in both inositol and glucose metabolism and fungal virulence.

How pathogens prioritize nutrients while adapting to changing environments is central to their survival and ability to cause disease. This study shows that the inositol-sensing receptor Itr4 enables Cryptococcus neoformans to maintain inositol use even when glucose is abundant, linking nutrient sensing to carbon metabolism and virulence.

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Cite

BibTeXRIS
BibTeX
@article{wang2026inositol,
  title = {{An inositol receptor Itr4 coordinates carbon catabolite regulation and virulence in Cryptococcus neoformans}},
  author = {Yina Wang and Robert J Tancer and Maggie Wear and Katrina M Jackson and Yu Zhang and Kan Li and Jun Wang and Yong-Gui Gao and Kirsten Nielsen and Arturo Casadevall and Chaoyang Xue},
  journal = {PLOS Biology},
  year = {2026},
  month = oct,
  doi = {10.1371/journal.pbio.3003709},
  url = {https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3003709},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - An inositol receptor Itr4 coordinates carbon catabolite regulation and virulence in Cryptococcus neoformans
AU  - Yina Wang
AU  - Robert J Tancer
AU  - Maggie Wear
AU  - Katrina M Jackson
AU  - Yu Zhang
AU  - Kan Li
AU  - Jun Wang
AU  - Yong-Gui Gao
AU  - Kirsten Nielsen
AU  - Arturo Casadevall
AU  - Chaoyang Xue
PY  - 2026
DA  - 2026/10/13
JO  - PLOS Biology
DO  - 10.1371/journal.pbio.3003709
UR  - https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3003709
AB  - Nutrient sensing and utilization are critical for microbes to adapt to their environment and evade predators. The encapsuled yeast Cryptococcus neoformans has a unique ability to sense and utilize the sugar inositol as both a signaling molecule and as a carbon source. This trait is advantageous not only in the natural environment but also to promote its pathogenesis, including invasion of the central nervous system. In this study, we have identified a novel inositol transporter-like receptor (transceptor) Itr4 that coordinates inositol and glucose metabolism by regulating inositol transporters (ITRs) and glucose sensor Hxs1. Itr4 binds inositol and regulates the function of other ITRs and its loss leads to a significant decrease in inositol uptake activity, resulting in a lack of mating, reduced capsule size, reduced blood–brain barrier (BBB) penetration, and virulence attenuation. Mutagenesis analysis of Itr4 protein identified an essential N-terminal tail and two amino acids, Q388 and Q389, as sites of functional importance. The ITR4Q388A, Q389A allele showed a dominant phenotype with increased inositol uptake, enlarged capsule and significantly attenuated virulence. In summary, we identify a new C. neoformans inositol transceptor, Itr4, the first such example in eukaryotes, with novel regulatory roles in both inositol and glucose metabolism and fungal virulence.  How pathogens prioritize nutrients while adapting to changing environments is central to their survival and ability to cause disease. This study shows that the inositol-sensing receptor Itr4 enables Cryptococcus neoformans to maintain inositol use even when glucose is abundant, linking nutrient sensing to carbon metabolism and virulence.
SN  - 1545-7885
SN  - 1544-9173
ER  -