Candida albicans is an opportunistic pathogen, which is a part of normal flora (commensal) in healthy individuals and can become invasive in immunocompromised patients with a 44% mortality rate. Iron is a significant cofactor for many enzymes that are essential for cellular functions both in human and C. albicans. Iron uptake during infection is thus considered as a virulence contributor to this fungus. In the previous study, we found that C. albicans Hap43 is essential for its growth under the low-iron condition which mimics the environment within the host. Deletion of HAP43 also attenuates the virulence of C. albicans in a mouse model of infection. In this study, we further characterized the functional domains of Hap43 to understand the molecular mechanism of iron-responsive gene regulation by Hap43. In silico domain prediction and sequence alignment of Hap43 showed that Hap43 contains a CCAAT-binding complex (CBC) binding domain (CBD), a bZIP domain, a NES peptide, a NLS peptide, and three cysteine-rich domains. The putative CBD and bZIP domains are both demonstrated to be essential for Hap43 normal function. We also proved that Hap43 possesses a C-terminal repression domain critical for gene repression in response to iron limitation. In addition, we displayed that the activity of the repression domain is regulated by a regulatory domain (RD) which is located between the two cysteine-rich domains. Furthermore, we provided the evidences that Hap43 cooperates with CBC to repress the gene expression and mediate the flavinogenesis under the low-iron condition. Together, CBC has general biological functions, while Hap43 functions mainly in the iron-limited condition.

中文摘要 I
Abstract II
致謝辭 III
Table of Contents IV
List of Tables VI
List of Figures VII
List of Supplemental Figures VIII

1. Introduction 1
1.1 Candida albicans: an important pathogen 1
1.2 The importance of the essential iron and microbial pathogen 2
1.3 The regulation of iron homeostasis in Saccharomyces cerevisiae 4
1.4 The iron uptake systems in C. albicans 6
1.5 The CCAAT-binding complex in fungi 7
1.6 The CCAAT-binding complex and Hap43 in C. albicans 10
2. Materials and methods 12
2.1 Yeast strains and growth conditions 12
2.2 Isolation of yeast genomic DNA 13
2.3 Yeast transformation 13
2.4 Candida one-hybrid assay 14
2.5 Gene disruption 17
2.6 Southern blot analysis 18
2.7 Generation of HAP43 truncated mutants 19
2.8 Growth-dependent spot assay 20
2.9 RNA isolation 20
2.10 Reverse transcription PCR (RT-PCR) and quantitative real-time PCR (q-PCR) 21
2.11 Flavin secretion assay 22
2.12 Candida two-hybrid assay 22
3. Results 25
3.1 C. albicans Hap43 contains multiple domains which are potentially involved in its activity 25
3.2 The region from CR3 to C-terminus of Hap43 possesses the repressive activity and is essential for C. albicans growth under the low-iron condition 27
3.3 The highly conserved Hap43 C-terminal region consisting of 67 amino acids is critical for C. albicans growth under the low-iron condition 29
3.4 The region between CR1 and CR2 participates in the iron-responsiveness and regulation of the repression activity of Hap43 30
3.5 The bZIP domain of Hap43 is essential for the growth of C. albicans under the iron-deprived condition 31
3.6 The CBC binding domain of Hap43 is essential for the growth of C. albicans under the iron-deprived condition. 32
3.7 Deleting either one component of the CBC impedes the growth of C. albicans under the iron-deprived condition 33
3.8 C. albicans CBC is essential for the repression of genes encoding iron-utilization proteins under the iron-deprived condition 33
3.9 C. albicans CBC is required for flavinogenesis in response to iron starvation 34
3.10 The CBC components interact with each other in vivo independently of iron level 35
3.11 C. albicans CBC potentially has both Hap43-dependent and -independent functions 36
4. Discussion 38
5. References 43

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