GLN3 Encodes a Global Regulator of Nitrogen Metabolism and Virulence of C. Albicans

Overview

Journal Fungal Genet Biol

Specialties Biology
Genetics
Microbiology

Date 2007 Oct 24

PMID 17950010

Citations 25

Authors

Wei-Li Liao

Ana M Ramon

William A Fonzi

Affiliations

Soon will be listed here.

Abstract

The function of GLN3, a GATA factor encoding gene, in nitrogen metabolism of Candida albicans was examined. GLN3 null mutants had reduced growth rates on multiple nitrogen sources. More severe growth defects were observed in mutants lacking both GLN3 and GAT1, a second GATA factor gene. GLN3 was an activator of two genes involved in ammonium assimilation, GDH3, encoding NADP-dependent glutamate dehydrogenase, and MEP2, which encodes an ammonium permease. GAT1 contributed to MEP2 expression, but not that of GDH3. A putative general amino acid permease gene, GAP2, was also activated by both GLN3 and GAT1, but activation by GLN3 was nitrogen source dependent. GLN3 was constitutively expressed, but GAT1 expression varied with nitrogen source and was reduced 2- to 3-fold in gln3 mutants. Both gln3 and gat1 mutants exhibited reduced sensitivity to rapamycin, suggesting they function downstream of TOR kinase. Hyphae formation by gln3 and gat1 mutants differed in relation to nitrogen source. The gln3 mutants formed hyphae on several nitrogen sources, but not ammonium or urea, suggesting a defect in ammonium assimilation. Virulence of gln3 mutants was reduced in a murine model of disseminated disease. We conclude that GLN3 has a broad role in nitrogen metabolism, partially overlapping, but distinct from that of GAT1, and that its function is important for the ability of C. albicans to survive within the host environment.

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References

Martinez P, Ljungdahl P . An ER packaging chaperone determines the amino acid uptake capacity and virulence of Candida albicans. Mol Microbiol. 2004; 51(2):371-84. DOI: 10.1046/j.1365-2958.2003.03845.x. View

Stanbrough M, Rowen D, MAGASANIK B . Role of the GATA factors Gln3p and Nil1p of Saccharomyces cerevisiae in the expression of nitrogen-regulated genes. Proc Natl Acad Sci U S A. 1995; 92(21):9450-4. PMC: 40819. DOI: 10.1073/pnas.92.21.9450. View

Kirsch D, Whitney R . Pathogenicity of Candida albicans auxotrophic mutants in experimental infections. Infect Immun. 1991; 59(9):3297-300. PMC: 258168. DOI: 10.1128/iai.59.9.3297-3300.1991. View

Marzluf G . Genetic regulation of nitrogen metabolism in the fungi. Microbiol Mol Biol Rev. 1997; 61(1):17-32. PMC: 232598. DOI: 10.1128/mmbr.61.1.17-32.1997. View

Platt A, Langdon T, Arst Jr H, Kirk D, Tollervey D, Sanchez J . Nitrogen metabolite signalling involves the C-terminus and the GATA domain of the Aspergillus transcription factor AREA and the 3' untranslated region of its mRNA. EMBO J. 1996; 15(11):2791-801. PMC: 450215. View

Garcia M, OConnor J, Garcia L, Martinez S, Herrero E, Del Castillo Agudo L . Isolation of a Candida albicans gene, tightly linked to URA3, coding for a putative transcription factor that suppresses a Saccharomyces cerevisiae aft1 mutation. Yeast. 2001; 18(4):301-11. DOI: 10.1002/1097-0061(20010315)18:4<301::AID-YEA672>3.0.CO;2-H. View

Teakle G, Gilmartin P . Two forms of type IV zinc-finger motif and their kingdom-specific distribution between the flora, fauna and fungi. Trends Biochem Sci. 1998; 23(3):100-2. DOI: 10.1016/s0968-0004(98)01174-8. View

Wilson R, Arst Jr H . Mutational analysis of AREA, a transcriptional activator mediating nitrogen metabolite repression in Aspergillus nidulans and a member of the "streetwise" GATA family of transcription factors. Microbiol Mol Biol Rev. 1998; 62(3):586-96. PMC: 98926. DOI: 10.1128/MMBR.62.3.586-596.1998. View

Tanzer M, Arst H, Skalchunes A, Coffin M, Darveaux B, Heiniger R . Global nutritional profiling for mutant and chemical mode-of-action analysis in filamentous fungi. Funct Integr Genomics. 2003; 3(4):160-70. DOI: 10.1007/s10142-003-0089-3. View

10.

Minehart P, MAGASANIK B . Sequence of the GLN1 gene of Saccharomyces cerevisiae: role of the upstream region in regulation of glutamine synthetase expression. J Bacteriol. 1992; 174(6):1828-36. PMC: 205784. DOI: 10.1128/jb.174.6.1828-1836.1992. View

11.

Ramon A, Porta A, Fonzi W . Effect of environmental pH on morphological development of Candida albicans is mediated via the PacC-related transcription factor encoded by PRR2. J Bacteriol. 1999; 181(24):7524-30. PMC: 94210. DOI: 10.1128/JB.181.24.7524-7530.1999. View

12.

Coffman J, Rai R, Loprete D, Cunningham T, Svetlov V, Cooper T . Cross regulation of four GATA factors that control nitrogen catabolic gene expression in Saccharomyces cerevisiae. J Bacteriol. 1997; 179(11):3416-29. PMC: 179131. DOI: 10.1128/jb.179.11.3416-3429.1997. View

13.

Magasanik B, Kaiser C . Nitrogen regulation in Saccharomyces cerevisiae. Gene. 2002; 290(1-2):1-18. DOI: 10.1016/s0378-1119(02)00558-9. View

14.

Cooper T . Transmitting the signal of excess nitrogen in Saccharomyces cerevisiae from the Tor proteins to the GATA factors: connecting the dots. FEMS Microbiol Rev. 2002; 26(3):223-38. PMC: 4384438. DOI: 10.1111/j.1574-6976.2002.tb00612.x. View

15.

Riego L, Avendano A, DeLuna A, Rodriguez E, Gonzalez A . GDH1 expression is regulated by GLN3, GCN4, and HAP4 under respiratory growth. Biochem Biophys Res Commun. 2002; 293(1):79-85. DOI: 10.1016/S0006-291X(02)00174-2. View

16.

Braun B, van het Hoog M, dEnfert C, Martchenko M, Dungan J, Kuo A . A human-curated annotation of the Candida albicans genome. PLoS Genet. 2005; 1(1):36-57. PMC: 1183520. DOI: 10.1371/journal.pgen.0010001. View

17.

Biswas K, Morschhauser J . The Mep2p ammonium permease controls nitrogen starvation-induced filamentous growth in Candida albicans. Mol Microbiol. 2005; 56(3):649-69. DOI: 10.1111/j.1365-2958.2005.04576.x. View

18.

Lorenz M, Bender J, Fink G . Transcriptional response of Candida albicans upon internalization by macrophages. Eukaryot Cell. 2004; 3(5):1076-87. PMC: 522606. DOI: 10.1128/EC.3.5.1076-1087.2004. View

19.

Pan H, Feng B, Marzluf G . Two distinct protein-protein interactions between the NIT2 and NMR regulatory proteins are required to establish nitrogen metabolite repression in Neurospora crassa. Mol Microbiol. 1998; 26(4):721-9. DOI: 10.1046/j.1365-2958.1997.6041979.x. View

20.

Meijer M, Boonstra J, Verkleij A, Verrips C . Glucose repression in Saccharomyces cerevisiae is related to the glucose concentration rather than the glucose flux. J Biol Chem. 1998; 273(37):24102-7. DOI: 10.1074/jbc.273.37.24102. View