Cryptococcus as a model for host-pathogen interactions
Pathogens adapt to their surroundings or hosts by adjusting cell developmental processes based on changing environmental conditions. Cell surface receptors on pathogens are essential for sensing extracellular signals and controlling intracellular signal transduction pathways that regulate cell development and virulence. My lab studies the human yeast pathogen Cryptococcus neoformans, the causative agent of life-threatening cryptococcal meningitis. C. neoformans is the leading cause of fungal meningitis with over 1 million cases annually in mostly immunocompromised individuals, such as those with HIV/AIDS, organ transplants, or those who are immunocompromised by cancer chemotherapy or by other treatments. As an experimental model organism, Cryptococcus allows us to study how human fungal pathogens sense extracellular signals that are important for their virulence.
- Functional analysis of G protein-coupled receptors (GPCRs). It is now well established that GPCR signaling is involved in a wide range of physiological processes and diseases, and this family of proteins plays a critical role in sensing extracellular signals. In fact, many proteins in this gene family have been developed as important drug targets for controlling a variety of human diseases. Our studies focus on GPCRs that sense nutrients, and how such interactions affect the regulation of downstream signal pathways, which control the virulence and cellular development of Cryptococcus.
- Role of inositol and inositol transporters in fungal development and virulence. Inositol is both a basal structural component of cells and an important signaling molecule involved in a variety of cell developmental processes. The C. neoformans genome contains an unusually large inositol transporter gene family that has been found to be important for fungal sexual reproduction and fungal virulence. Our recent studies link fungal inositol acquisition to brain infection in animal models, which correlates with the fact that human and animal brains contain abundant free inositol. We propose that inositol plays an important role in the development of cryptococcal meningitis, the predominant and most lethal form of cryptococcosis. An understanding of how inositol is involved in fungal brain infection could have significant impact on understanding of its disease mechanism.
- Protein ubiquitination and fungal virulence. E3 ubiquitin ligases play an essential role in regulation of many cellular processes, and are considered to be an important new drug target platform for future mechanism-driven drug discovery. We recently identified Fbp1, a key F-box protein of an SCF (Skp1, Cullin, F-box protein) E3 ubiquitin ligase complex that is essential for C. neoformans to cause disease. We are investigating how this SCFFBP1 E3 ubiquitin ligase is involved in fungal development and fungal virulence, and what are the responsible substrates. We will also extend our study to analyze other F-box proteins in Cryptococcus.
By applying a combination of genetics, biochemistry, and molecular biology, the goal of our research is to gain new insights into fungal-host interactions. The information should lead to novel drug targets, as well as better approaches for diagnosis and control of fungal diseases.
Masso-Silva J, Espinosa V, Liu TB, Wang Y, Xue C, Rivera A (2018) The F-Box Protein Fbp1 Shapes the Immunogenic Potential of Cryptococcus neoformans. MBio 9. PMI: 29317510
Liao G, Wang Y, Liu TB, Kohli G, Qian W, Shor E, Subbian S, Xue C (2018) Role of the inositol pyrophosphate multikinase Kcs1 in Cryptococcus inositol metabolism. Fungal Genet Biol. PMI: 29357302
Boyce KJ, Wang Y, Verma S, Shakya VPS, Xue C, Idnurm A (2017) Mismatch Repair of DNA Replication Errors Contributes to Microevolution in the Pathogenic Fungus Cryptococcus neoformans. MBio 8. PMI: 28559486
Huang W, Liao G, Baker GM, Wang Y, Lau R, Paderu P, Perlin DS, Xue C (2016) Lipid flippase subunit Cdc50 mediates drug resistance and virulence in Cryptococcus neoformans. MBio 7: e00478-00416. PMI: 27165800
Ero R, Dimitrova VT, Chen Y, W. B, Feng S, Liu T, Wang P, Xue C, Tan SM, Gao Y-G (2015) Crystal structure of Gib2, a signal-transducing protein scaffold associated with ribosomes in Cryptococcus neoformans. Scientific Reports 5: 8688. PMI:
Liu TB, Xue C (2014) Fbp1-mediated ubiquitin-proteasome pathway controls Cryptococcus neoformans virulence by regulating fungal intracellular growth in macrophages. Infect Immun 82: 557-568. PMI: 24478071
Liu TB, Subbian S, Pan W, Eugenin E, Xie J, Xue C (2014) Cryptococcus inositol utilization modulates the host protective immune response during brain infection. Cell Commun Signal 12: 51. PMI: 25201772
Liu TB, Wang Y, Baker GM, Fahmy H, Jiang L, Xue C (2013) The glucose sensor-like protein Hxs1 is a high-affinity glucose transporter and required for virulence in Cryptococcus neoformans. PLoS ONE 8: e64239. PMI:
Liu TB, Kim JC, Wang Y, Toffaletti DL, Eugenin E, Perfect JR, Kim KJ, Xue C (2013) Brain inositol is a novel stimulator for promoting Cryptococcus penetration of the blood-brain barrier. PLoS Pathog 9: e1003247. PMI: 23592982
Xue C (2012) Cryptococcus and beyond – Inositol utilization and its implications for the emergence of fungal virulence. . PLoS Pathogens 8: e1002869. PMI:
Magditch DA, Liu, T.B., Xue, C., and Idnurm, A (2012) DNA mutations mediate microevolution between host-adapted forms of the pathogenic fungus Cryptococcus neoformans. PLoS Pathogens 8: e1002936. PMI:
Wang Y, Liu TB, Patel S, Jiang L, Xue C (2011) The casein kinase I protein Cck1 regulates multiple signaling pathways and is essential for cell integrity and fungal virulence in Cryptococcus neoformans. Eukaryot Cell 10: 1455-1464. PMI: 21926330
Wang Y, Liu TB, Delmas G, Park S, Perlin D, Xue C (2011) Two major inositol transporters and their role in cryptococcal virulence. Eukaryot Cell 10: 618-628. PMI: 21398509
Okagaki LH, Wang Y, Ballou ER, O’Meara TR, Bahn YS, Alspaugh JA, Xue C, Nielsen K (2011) Cryptococcal titan cell formation is regulated by G-protein signaling in response to multiple stimuli. Eukaryot Cell 10: 1306-1316. PMI: 21821718
Liu TB, Wang Y, Stukes S, Chen Q, Casadevall A, Xue C (2011) The F-Box protein Fbp1 regulates sexual reproduction and virulence in Cryptococcus neoformans. Eukaryot Cell 10: 791-802. PMI: 21478432
Xue C, Wang Y, Hsueh YP (2010) Assessment of constitutive activity of a G protein-coupled receptor, CPR2, in Cryptococcus neoformans by heterologous and homologous methods. Methods Enzymol 484: 397-412. PMI: 21036243
Xue C, Liu T, Chen L, Li W, Liu I, Kronstad JW, Seyfang A, Heitman J (2010) Role of an expanded inositol transporter repertoire in Cryptococcus neoformans sexual reproduction and virulence. MBio 1. PMI: 20689743
Hsueh YP, Xue C, Heitman J (2009) A constitutively active GPCR governs morphogenic transitions in Cryptococcus neoformans. EMBO J 28: 1220-1233. PMI: 19322200
Xue C, Hsueh YP, Heitman J (2008) Magnificent seven: roles of G protein-coupled receptors in extracellular sensing in fungi. FEMS Microbiol Rev 32: 1010-1032. PMI: 18811658
Xue C, Hsueh YP, Chen L, Heitman J (2008) The RGS protein Crg2 regulates both pheromone and cAMP signalling in Cryptococcus neoformans. Mol Microbiol 70: 379-395. PMI: 18761692
Xue C, Tada Y, Dong X, Heitman J (2007) The human fungal pathogen Cryptococcus can complete its sexual cycle during a pathogenic association with plants. Cell Host Microbe 1: 263-273. PMI: 18005707
Xue C, Bahn YS, Cox GM, Heitman J (2006) G protein-coupled receptor Gpr4 senses amino acids and activates the cAMP-PKA pathway in Cryptococcus neoformans. Mol Biol Cell 17: 667-679. PMI: 16291861