title: The glucose sensor-like protein Hxs1 is a high-affinity glucose transporter and required for virulence in Cryptococcus neoformans.
abstract: Cryptococcus is a major fungal pathogen that frequently causes systemic infection in patients with compromised immunity. Glucose, an important signal molecule and the preferred carbon source for Cryptococcus, plays a critical role in fungal development and virulence. Cryptococcus contains more than 50 genes sharing high sequence homology with hexose transporters in Saccharomyces cerevisiae. However, there is no report on their function in glucose sensing or transport. In this study, we investigated two hexose transporter-like proteins (Hxs1 and Hxs2) in Cryptococcus that share the highest sequence identity with the glucose sensors Snf3 and Rgt2 in S. cerevisiae. The expression of HXS1 is repressed by high glucose, while the HXS2 expression is not regulated by glucose. Functional studies showed that Hxs1 is required for fungal resistance to oxidative stress and fungal virulence. The hxs1Δ mutant exhibited a significant reduction in glucose uptake activity, indicating that Hxs1 is required for glucose uptake. Heterologous expression of Cryptococcus HXS1 rendered the S. cerevisiae mutant lacking all 20 hexose transporters a high glucose uptake activity, demonstrating that Hxs1 functions as a glucose transporter. Heterologous expression of HXS1 in the snf3Δ rgt2Δ double mutant did not complement its growth in YPD medium containing the respiration inhibitor antimycin A, suggesting that Hxs1 may not function as a glucose sensor. Taken together, our results demonstrate that Hxs1 is a high-affinity glucose transporter and required for fungal virulence.
authors.affiliation: Public Health Research Institute Center, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA.
authors.forename: Tong-Bao
authors.initials: TB
authors.lastname: Liu
authors.forename: Yina
authors.initials: Y
authors.lastname: Wang
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Baker
authors.forename: Hany
authors.initials: H
authors.lastname: Fahmy
authors.forename: Linghuo
authors.initials: L
authors.lastname: Jiang
authors.forename: Chaoyang
authors.initials: C
authors.lastname: Xue
mesh_terms: D000968:Antimycin A / Q000494:pharmacology; D001692:Biological Transport; D003455:Cryptococcus neoformans / Q000166:cytology / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D051246:Glucose Transport Proteins, Facilitative / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009004:Monosaccharide Transport Proteins / Q000737:chemistry; D009154:Mutation; D018384:Oxidative Stress; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000254:growth & development; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry; D017386:Sequence Homology, Amino Acid
chemical_list: D005656:Fungal Proteins; D051246:Glucose Transport Proteins, Facilitative; D009004:Monosaccharide Transport Proteins; C112512:RGT2 protein, S cerevisiae; C104463:SNF3 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D000968:Antimycin A; D005947:Glucose