Candida albicans is one of the most frequently isolated fungal pathogens of humans. It can undergo reversible morphogenetic transitions between budding yeast, pseudohyphal, and hyphal growth forms. Its unique ability to switch from yeast to hyphal growth in response to various host and environmental signals is essential to its pathogenicity. Many hypha-specific genes encode virulence factors. Hyphal development is regulated by multiple signal transduction pathways. Among them, the cAMP-dependent protein kinase A (PKA) pathway is a major regulator of morphogenesis and virulence. Despite its importance, the molecular mechanism for how the cAMP-PKA pathway activates the hyphal transcriptional program is still not known. We find cAMP- PKA dependent down-regulation of the major repressor of hyphal morphogenesis, Nrg1, correlates with the initiation of the hyphal transcriptional program. Sustained hyphal transcription requires Hda1 being recruited to the promoters of hypha-specific genes, where it leads to changes in promoter chromatin. We propose to determine the mechanisms and regulators for cAMP-PKA dependent Nrg1 down-regulation upon hyphal induction in Aim 1.
Aim 2 defines host factor(s) and C. albicans pathways for the promoter recruitment of Hda1 and its importance in invasive candidiasis.
Aim 3 studies functions and regulation of Cph2. A combined approach using molecular genetics, cell biology and biochemistry will be taken in our studies. This work will provide us with a better understanding of how C. albicans integrates various signals to control growth and development, and how it survives and grows in various host environments.

Public Health Relevance

Candida has emerged as a significant human pathogen. It causes common mucosal manifestations such as oropharyngeal thrush and vaginitis. In hospitalized patients, disseminated candidiasis is the fourth most common infection (outpacing all gram- negative species) and carries a mortality rate in excess of 30%. Development of the next generation of antifungal agents will require a further understanding of the biology of Candida.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM055155-17
Application #
8523904
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Gaillard, Shawn R
Project Start
1997-01-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
17
Fiscal Year
2013
Total Cost
$332,343
Indirect Cost
$115,125
Name
University of California Irvine
Department
Biochemistry
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Guan, Zhiyun; Liu, Haoping (2015) Overlapping Functions between SWR1 Deletion and H3K56 Acetylation in Candida albicans. Eukaryot Cell 14:578-87
Guan, Zhiyun; Liu, Haoping (2015) The WOR1 5' untranslated region regulates white-opaque switching in Candida albicans by reducing translational efficiency. Mol Microbiol 97:125-38
Lane, Shelley; Di Lena, Pietro; Tormanen, Kati et al. (2015) Function and Regulation of Cph2 in Candida albicans. Eukaryot Cell 14:1114-26
Lu, Yang; Su, Chang; Liu, Haoping (2014) Candida albicans hyphal initiation and elongation. Trends Microbiol 22:707-14
Lu, Yang; Su, Chang; Solis, Norma V et al. (2013) Synergistic regulation of hyphal elongation by hypoxia, CO(2), and nutrient conditions controls the virulence of Candida albicans. Cell Host Microbe 14:499-509
Stevenson, John S; Liu, Haoping (2013) Nucleosome assembly factors CAF-1 and HIR modulate epigenetic switching frequencies in an H3K56 acetylation-associated manner in Candida albicans. Eukaryot Cell 12:591-603
Su, Chang; Lu, Yang; Liu, Haoping (2013) Reduced TOR signaling sustains hyphal development in Candida albicans by lowering Hog1 basal activity. Mol Biol Cell 24:385-97
Stevenson, John S; Liu, Haoping (2011) Regulation of white and opaque cell-type formation in Candida albicans by Rtt109 and Hst3. Mol Microbiol 81:1078-91
Wang, Allen; Raniga, Prashna Pala; Lane, Shelley et al. (2009) Hyphal chain formation in Candida albicans: Cdc28-Hgc1 phosphorylation of Efg1 represses cell separation genes. Mol Cell Biol 29:4406-16
Lu, Yang; Su, Chang; Mao, Xuming et al. (2008) Efg1-mediated recruitment of NuA4 to promoters is required for hypha-specific Swi/Snf binding and activation in Candida albicans. Mol Biol Cell 19:4260-72

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