Table 2. Gene regulatory events mediated by Sef1-, Sfu1-, and Hap43.
Direct gene regulatory targets of Sef1, Sfu1, and/or Hap43 are presented with descriptions, published virulence associations, fold expression changes, and physically-associated transcription factor. sfu1ΔΔ was assessed under iron-replete conditions, and sef1ΔΔ and hap43ΔΔ under iron-depleted conditions. Citations for published virulence associations are: FTR1 (Ramanan and Wang, 2000), CFL2 (Noble et al., 2010), HAP43 (Hsu et al., 2011), orf19.4905 (Noble et al., 2010), SEF1 (Noble et al., 2010), HMX1 (Navarathna and Roberts), HEM3 (Kirsch and Whitney, 1991), CAT1 (Nakagawa et al., 2003), and ICL1 (Barelle et al., 2006; Lorenz and Fink, 2001; Ramirez and Lorenz, 2007).
| REGULATED GENE | Wild type expression (replete vs. low iron) |
C. albicans Transcription Factor | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Systematic name |
Gene name |
Description | Cellular process | Role in virulence? (VIR) |
Sfu1 | Sef1 | Hap43 | ||||
| Expression (sfu1ΔΔ vs. WT) |
Promoter binding (Sfu1) | Expression (sef1ΔΔ vs. WT) |
Promoter binding (Sef1) |
Expression (hap43ΔΔ vs. WT) |
Promoter binding (Hap43) |
||||||
| orf19.539 | LAP3 | Putative ortholog of S.c. Lap3, a cysteine aminopeptidase that protects against homocysteine toxicity | Metabolism | −100.9 | −2.63 | Sef1 | −2.5 | ||||
| orf19.7114 | CSA1 | Surface antigen on elongating hyphae and buds | Cell wall composition: protein | −64.6 | −52.46 | Sef1 | −9.2 | ||||
| orf19.1263 | CFL1 | Putative ferric reductase, with sequence similarity to S.c. Fre2 which with Fre1 is a major cellular ferric reductase | Iron uptake: ferric reductase | −42.9 | 45.6 | −4.81 | Sef1 | 2.3 | |||
| orf19.5636 | RBT5 | GPI-anchored cell wall protein involved in hemoglobin utilization | Iron uptake: heme utilization pathway | −41.1 | 14.1 | Sfu1 | −2.39 | Sef1 | |||
| orf19.3117 | CSA2 | Putative cell surface protein | Cell wall composition: protein | −39.5 | 6.3 | −26.79 | Sef1 | −15.2 | |||
| orf19.5634 | FRP1 | Putative ferric reductase, with sequence similarity to S.c. Fre5 | Iron uptake: ferric reductase | −36.6 | 20.6 | Sfu1 | −5.78 | Sef1 | −3.2 | ||
| orf19.1930 | CFL5 | Putative ferric reductase, with similarity to S.c. Fre3 | Iron uptake: ferric reductase | −34.9 | 22.9 | −32.80 | Sef1 | 4.2 | |||
| orf19.5952 | Conserved hypothetical protein | Unknown | −32.5 | −46.24 | Sef1 | ||||||
| orf19.2179 | SIT1 | Transporter of ferrichrome siderophores, but not ferrioxamine B; putative ortholog of S.c. Arn1 | Iron uptake: siderophore transporter | −27.0 | 12.1 | Sfu1 | −3.16 | Sef1 | −4.1 | ||
| orf19.4802 | FTH1 | Putative ortholog of S.c. Fth1 high affinity iron transporter for intravacuolar iron stores | Iron homeostasis: vacuolar transporter | −22.4 | 22.6 | Sfu1 | |||||
| orf19.3538 | FRE9 | Putative ferric reductase with similarity to S.c. Fre3 | Iron uptake: ferric reductase | −20.0 | 8.9 | Sfu1 | −4.44 | Sef1 | −2.2 | ||
| orf19.7219 | FTR1 | High-affinity iron permease, putative ortholog of S.c. Ftr1 | Iron uptake: reductive pathway | VIR | −17.6 | 14.4 | Sfu1 | −2.94 | Sef1 | ||
| orf19.4647 | HAP3 | Conserved hypothetical protein with similarity to S.c. Hap3, a subunit of the Hap2p/3p/4p/5p CCAAT-binding complex | Iron regulation: transcription factor | −17.5 | −23.25 | Sef1 | −2.7 | ||||
| orf19.1264 | CFL2 | Putative ferric reductase with sequence similarity to S.c. Fre4 | Iron uptake: ferric reductase | VIR | −17.3 | 21.2 | −7.10 | Sef1 | 2.3 | ||
| orf19.5635 | PGA7 | Putative hyphal surface antigen with predicted GPI anchor | Cell wall composition: protein | −12.5 | 5.8 | Sfu1 | −4.70 | Sef1 | −2.9 | ||
| orf19.334 | Hypothetical protein, conserved in C.d., C.t. | Unknown | −9.7 | −2.01 | Sef1 | ||||||
| orf19.4795 | Conserved hypothetical protein | Unknown | −8.4 | −2.85 | Sef1 | −2.3 | |||||
| orf19.7112 | FRP2 | Putative ferric reductase, with sequence similarity to S.c. Fre5 | Iron uptake: ferric reductase | −7.2 | −4.40 | Sef1 | −2.6 | Hap43 | |||
| orf19.4270 | Putative mannosyltransferase | Cell wall composition: mannosylation | −5.2 | −6.17 | Sef1 | −6.4 | |||||
| orf19.5801 | RNR21 | Putative ortholog of S.c. Rnr2, a component of ribonucleotide-diphosphate reductase that catalyzes the rate-limiting step in dNTP synthesis | Metabolism: biosynthesis of dNTPs | −5.0 | −2.58 | Sef1 | −2.2 | ||||
| orf19.6793 | Putative protein conserved in C.d. and C.t. | Unknown | −5.0 | −4.35 | Sef1 | −4.7 | |||||
| orf19.681 | HAP43 | CCAAT-binding factor (CBF)-associated transcription factor required for iron-limitation response, | Iron regulation: transcription factor | −4.6 | 3.8 | −3.06 | Sef1 | (−26.0) | |||
| orf19.1228 | HAP2 | Putative ortholog of S.c. Hap2, a component of CCAAT-binding factor | Transcription: transcription factor | −4.5 | −3.33 | Sef1 | −2.2 | ||||
| orf19.5475 | Hypothetical protein | Unknown | −4.4 | 3.2 | Sfu1 | −2.08 | −2.2 | ||||
| orf19.4905 | Putative MFS transporter | Transporter | VIR | −4.4 | −5.39 | Sef1 | −2.1 | ||||
| orf19.3859 | Putative ortholog of S.c. Ifa38, a microsomal beta-keto-reductase important for VLCFA synthesis | Metabolism: biosynthesis of lipids | −4.1 | −2.43 | Sef1 | −2.1 | |||||
| orf19.7218 | RBE1 | Putative cell wall protein, no predicted GPI anchor | Cell wall composition: protein | −4.1 | −4.03 | Sef1 | −4.0 | ||||
| orf19.4211 | FET3 | Multicopper oxidase with similarity to S.c. Fet3 | Iron uptake: reductive pathway | −4.0 | 3.2 | −10.47 | Sef1 | ||||
| orf19.4735 | Putative ornithine cyclodeaminase, putative ortholog of S.c. YGL159W | Metabolism: interconversion of amino acids | −3.9 | −4.85 | Sef1 | −2.9 | Hap43 | ||||
| orf19.2062 | SOD4 | Member of a family of superoxide dismutases, predicted GPI-anchor | Response to stress: oxidative, cell wall composition: protein | −3.7 | −3.71 | Sef1 | −2.6 | ||||
| orf19.853 | SAP99 | Putative secreted aspartyl protease | Secreted enzyme | −3.7 | −2.38 | Sef1 | −2.1 | ||||
| orf19.5779 | RNR1 | Putative ortholog of S.c. Rnr1, a regulatory component of ribonucleotide reductase | Metabolism: biosynthesis of dNTPs | −3.7 | −5.25 | Sef1 | −3.1 | ||||
| orf19.411 | Conserved hypothetical protein | Unknown | −3.7 | −2.56 | Sef1 | −2.2 | |||||
| orf19.4328 | CCC2 | Copper-transporting P-type ATPase of Golgi that is required for wild-type iron assimilation, putative ortholog of S.c. Ccc2 | Iron uptake: reductive pathway | −3.6 | 3.0 | −3.53 | Sef1 | ||||
| orf19.6482 | Conserved hypothetical protein | Unknown | −3.6 | −2.71 | Sef1 | ||||||
| orf19.2177 | Hypothetical protein | Unknown | −3.6 | −6.84 | Sef1 | −2.3 | |||||
| orf19.1932 | CFL4 | Putative ortholog of S.c. Fre3, a ferric reductase | Iron uptake: ferric reductase | −3.6 | 24.4 | Sfu1 | 19.5 | ||||
| orf19.7445 | Putative ortholog of S.c. Vid24, a peripheral membrane protein located at Vid (vacuole import and degradation) vesicles | Vacuolar function | −3.5 | −2.79 | Sef1 | ||||||
| orf19.6832 | Conserved hypothetical protein with K-Cl cotransporter domain | Transporter: ions | −3.3 | −2.23 | Sef1 | ||||||
| orf19.4145 | ZCF20 | Putative zinc finger transcription factor | Transcription: transcription factor | −3.3 | −2.63 | Sef1 | |||||
| orf19.3753 | SEF1 | Putative transcription factor with zinc cluster DNA-binding motif, ortholog of S.c. Sef1 | Iron regulation: transcription factor | VIR | −3.0 | 5.4 | Sfu1 | −8.89 | |||
| orf19.335 | Conserved hypothetical protein | Unknown | −2.9 | −2.49 | Sef1 | ||||||
| orf19.6073 | HMX1 | Heme oxygenase, acts in utilization of hemin iron, putative ortholog of S.c. Hmx1 | Iron uptake: heme utilization pathway | VIR | −2.9 | −4.52 | Sef1 | −6.8 | |||
| orf19.22 | Conserved hypothetical protein with homology to peroxisomal membrane proteins | Peroxisomal function | −2.7 | −3.16 | Sef1 | ||||||
| orf19.1588 | Putative ortholog of S.c. Fmp21, a mitochondrial protein of unknown function | Mitochondrial function | −2.7 | −2.72 | Sef1 | ||||||
| orf19.2059 | Conserved hypothetical protein with homology to magnesium-dependent endonucleases and phosphatases involved in intracellular signalling | Signaling | −2.6 | −2.70 | Sef1 | ||||||
| orf19.4743 | AFG1 | Conserved hypothetical protein with similarity to S.c. Afg1 mitochondrial ATPase | Mitochondrial function | −2.4 | −3.19 | Sef1 | |||||
| orf19.1942 | SGE1 | Putative MFS-MDR transporter | Transporter | −2.4 | −2.52 | Sef1 | |||||
| orf19.1926 | SEF2 | Putative zinc cluster protein | Transcription: transcription factor | 2.2 | −12.54 | Sef1 | 9.0 | Hap43 | |||
| orf19.4869 | SFU1 | Transcriptional regulator of iron-responsive genes | Iron regulation: transcription factor | 3.5 | −17.1 | 5.9 | Hap43 | ||||
| orf19.6550 | Putative ortholog of S.c. Yor228c, a mitochondrial outer membrane protein | Mitochondrial function | 3.7 | 2.9 | Hap43 | ||||||
| orf19.6948 | CCC1 | Putative vacuolar Fe2+/Mn2+ transporter | Iron storage: vacuolar, Transporter: ions | 3.8 | 2.6 | Hap43 | |||||
| orf19.1742 | HEM3 | Hydroxymethylbilane synthase (uroporphyrinogen I synthase) | Iron utilization: biosynthesis of heme | VIR | 3.8 | −2.67 | Sef1 | 8.5 | Hap43 | ||
| orf19.7056 | Putative amino acid permease | Transporter: amino acids | 4.0 | 4.6 | 5.2 | Hap43 | |||||
| orf19.6229 | CAT1 | Catalase; role in resistance to oxidative stress, neutrophils, peroxide | Resistance to stress: oxidation | VIR | 4.2 | 2.0 | 10.6 | Hap43 | |||
| orf19.3034 | RLI1 | Putative ortholog of S.c. Rli1, an iron-sulfur protein required for ribosome biogenesis and translation initiation | Translation: initiation, ribosome biogenesis; iron utilization: iron-sulfur cluster protein | 4.5 | 3.9 | Hap43 | |||||
| orf19.5521 | ISA1 | Conserved hypothetical protein with strong similarity to S.c. Isa1, a mitochondrial matrix protein involved in biogenesis of iron-sulfur (Fe/S) cluster proteins | Iron utilization: biogenesis of iron-sulfur cluster proteins, mitochondrial function | 4.9 | 10.1 | Hap43 | |||||
| orf19.4099 | ECM17 | Putative ortholog of S.c. Met5, a sulfite reductase beta subunit | Metabolism: biosynthesis of amino acids | 5.1 | 2.01 | 13.4 | Hap43 | ||||
| orf19.6385 | ACO1 | Putative ortholog of S.c. Aco1, an aconitase required for the TCA cycle and maintenance of the mitochondrial genome | Metabolism: TCA cycle, mitochondrial function | 5.4 | 49.9 | Hap43 | |||||
| orf19.6257 | GLT1 | Putative ortholog of S.c. Glt1, an NAD(+)-dependent glutamate synthase | Metabolism: biosynthesis of glutamate | 5.7 | 7.2 | Hap43 | |||||
| orf19.1770 | CYC1 | Cytochrome c | Mitochondrial electron transport chain | 8.4 | 16.4 | Hap43 | |||||
| orf19.7498 | LEU1 | Putative ortholog of S.c. Leu1, an isopropylmalate isomerase that catalyzes the second step in the leucine biosynthesis pathway | Metabolism: biosynthesis of amino acids | 8.7 | 20.4 | Hap43 | |||||
| orf19.238 | CCP1 | Putative ortholog of S.c. Ccp1, a mitochondrial cytochrome-c oxidase | Mitochondrial function | 9.0 | 26.9 | Hap43 | |||||
| orf19.4040 | ILV3 | Putative ortholog of S.c. Ilv3, a dihydroxyacid dehydratase involved in biosynthesis of branched chain amino acids | Metabolism: biosynthesis of amino acids | 9.6 | 6.2 | Hap43 | |||||
| orf19.4674.1 | CRD2 | Metallothionein | Resistance to stress: copper | 24.9 | 3.3 | Hap43 | |||||
| orf19.4716 | GDH3 | Putative ortholog of S.c. Gdh3, a NADP(+)-dependent glutamate dehydrogenase that synthesizes glutamate from ammonia and alpha-ketoglutarate | Metabolism: biosynthesis of glutamate | −6.13 | Sef1 | ||||||
| orf19.1486 | Conserved hypothetical protein | Unknown | −3.48 | Sef1 | |||||||
| orf19.2602 | OPT1 | Oligopeptide transporter; transports 3-to-5-residue peptides | Transporter: peptides | −3.34 | Sef1 | −4.6 | |||||
| orf19.4673 | BMT9 | Putative beta-mannosyltransferase | Cell wall composition: mannosylation | −3.26 | −2.6 | Hap43 | |||||
| orf19.1027 | PDR16 | Phosphatidylinositol transfer protein, putative ortholog of S.c. Pdr16 that controls levels of various lipids | Metabolism: regulation of lipids | −2.98 | Sef1 | ||||||
| orf19.3610 | Conserved hypothetical protein with LgrB domain associated with murein hydrolase activity and penicillin tolerance | Unknown | −2.83 | Sef1 | |||||||
| orf19.2178 | Putative ortholog of S.c. Mrs4, an iron transporter that mediates Fe2+ transport across the inner mitochondrial membrane under low iron conditions | Iron utilization: mitochondrial transporter | −2.73 | Sef1 | |||||||
| orf19.6548 | ISU1 | Putatvie ortholog of S.c. Isu1, mitochondrial matrix protein that performs a scaffolding function during assembly of iron-sulfur clusters | Iron utilization: biogenesis of iron-sulfur cluster proteins, mitochondrial function | −2.57 | Sef1 | 2.0 | |||||
| orf19.3554 | AAT1 | Putative aspartate aminotransferase | Metabolism | −2.54 | Sef1 | −2.3 | |||||
| orf19.5137 | Hypothetical protein | Unknown | −2.54 | Sef1 | −4.1 | ||||||
| orf19.7244 | Conserved hypothetical protein with homology to fumarylacetoacetate (FAA) hydrolases | Unknown | −2.50 | Sef1 | 3.1 | ||||||
| orf19.3040 | EHT1 | Putative ortholog of S.c. Eht1, an Acyl-coenzymeA:ethanol O-acyltransferase that plays a minor role in medium-chain fatty acid ethyl ester biosynthesis | Metabolism: biosynthesis of lipids | −2.50 | Sef1 | ||||||
| orf19.1077 | ATM1 | Putative ortholog of S.c. Atm1, a mitochondrial inner membrane ABC transporter | Mitochondrial function, transporter | −2.30 | Sef1 | 2.9 | |||||
| orf19.1438 | Conserved hypothetical protein with homology to NADH dehydrogenase, FAD-containing subunit | Unknown | −2.27 | Sef1 | |||||||
| orf19.2862 | RIB1 | Putative ortholog of S.c. Rib1, a GTP cyclohydrolase II that catalyzes the first step of the riboflavin biosynthesis | Metabolism: biosynthesis of cofactors | −2.12 | Sef1 | ||||||
| orf19.1927 | SNM1 | Conserved hypothetical protein with Rpr2 motif of Rnase MRP family members | Translation: rRNA processing | −2.04 | Sef1 | 3.2 | Hap43 | ||||
| orf19.4012 | PCL5 | Putative cyclin | Cell cycle | −2.02 | Sef1 | −2.5 | |||||
| orf19.6399 | ATS1 | Putative ortholog of S.c. Ats1, a protein required, with Elongator complex, Kti11p, and Kti12p, for modification of wobble nucleosides in tRNA | Translation: tRNA modification | −2.01 | Sef1 | ||||||
| orf19.6844 | ICL1 | Putative ortholog of S.c. Icl1, a key enzyme of the glyoxylate cycle | Metabolism: glyoxylate cycle | VIR | 15.04 | Sef1 | 32.9 | ||||
| orf19.4679 | AGP2 | Putative ortholog of S.c. Agp2, an amino acid permease | Transporter: polyamines | −2.1 | Hap43 | ||||||
| orf19.516 | Putative ortholog of S.c. Rft1, a protein required for translocation of Man5GlcNac2-PP-Dol from the cytoplasmic side to the lumenal side of the ER membrane | Cell wall composition: N-glycosylation | 2.1 | Hap43 | |||||||
| orf19.4676 | Conserved hypothetical protein with homology to mitochondrial intermembrane space proteins | Mitochondrial function | 2.2 | Hap43 | |||||||
| orf19.93 | Putative ortholog of S.c. Mic17, a mitochondrial intermembrane space protein | Mitochondrial function | 2.2 | Hap43 | |||||||
| orf19.4041 | Putative ortholog of S.c. Pex4, a peroxisomal ubiquitin conjugating enzyme | Peroxisome function | 2.2 | Hap43 | |||||||
| orf19.517 | HAP31 | Putative ortholog of S.c. Hap3, a subunit of the CCAAT-binding complex | Iron regulation: transcription factor | 2.7 | Hap43 | ||||||
| orf19.2825 | Putative ortholog of S.c. Dre2, a protein required for iron-sulfur cluster assembly and sister chromatid cohesion | Iron utilization: iron-sulfur cluster assembly | 3.3 | Hap43 | |||||||
| orf19.2149 | Putative ortholog of S.c. Ypr003c, a putative sulfate permease | Transporter: sulfate | 3.3 | Hap43 | |||||||