The glucose sensor-like protein Hxs1 is a high-affinity glucose transporter and required for virulence in Cryptococcus neoformans.

Tong-Bao Liu,Yina Wang,Chaoyang Xue,Gregory M Baker,Linghuo Jiang,Hany Fahmy,Yong-Sun Bahn

doi:10.1371/journal.pone.0064239

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.

Highlights

The ability of a pathogen to sense extracellular signals and adapt to the host environment is essential for the establishment of an infection during a host-pathogen interaction
Our results showed that the hxs1D mutant had significantly lower glucose uptake activity than the wild type or the complemented strain, suggesting that Hxs1 plays a major role in glucose uptake (Fig. 4A)
Hxs1 is Required for Fungal Virulence Because the importance of glucose for fungal cellular development and the importance of Hxs1 in stress response and melanin production, we examined the potential impact of Hxs1 on fungal virulence using a murine inhalation infection model of cryptococcosis

Summary

Introduction

The ability of a pathogen to sense extracellular signals and adapt to the host environment is essential for the establishment of an infection during a host-pathogen interaction. Characterization of extracellular signals and their sensors in a pathogen is central for understanding its pathogenesis. Cryptococcus neoformans is a major human fungal pathogen and the causative agent of the often fatal cryptococcal meningoencephalitis, which is an AIDS-defining illness [1]. Cryptococcus, a haploid yeast pathogen, is an ideal model system to study signal transduction in pathogenic fungi. Several signaling pathways important for Cryptococcus virulence have been identified [2,3,4,5]. Extracellular signals and their sensors remain largely unknown

Methods

Results

Conclusion