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An Overview of the CCAAT-Box Binding Factor in Filamentous Fungi: Assembly, Nuclear Translocation, and Transcriptional Enhancement

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An Overview of the CCAAT-Box Binding Factor in Filamentous Fungi: Assembly, Nuclear Translocation, and Transcriptional Enhancement Biosci. Biotechnol. Biochem., 69 (4), 663–672, 2005 Review An Overview of the CCAAT-Box Binding Factor in Filamentous Fungi: Assembly, Nuclear Translocation, and Transcriptional Enhancement Masashi KATO Department of Biological Mechanisms and Functions, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan Filamentous fungi are frequently used for the pro- of amylolytic genes have been extensively studied on duction of industrial enzymes, since they produce a the A. oryzae taaG2 gene. Using a hybrid model system variety of enzymes including polysaccharide-degrading of A. nidulans transformed by the A. oryzae taaG2 gene, enzymes. Among the many filamentous fungi, Aspergil- we found that three factors, CCAAT-box binding lus species, such as A. oryzae and A. niger, are known as protein, CreA, and AmyR, are involved in taaG2 gene strong producers of amylolytic enzymes. We have been expression and regulation (Fig. 1).1–9) studying on the regulatory mechanisms underlying the The CCAAT-box binding protein binds to a CCAAT expression of A. oryzae amylolytic genes. Based on sequence at approximately À300 in the taaG2 promoter analyses using a hybrid model system of A. nidulans and is responsible for high-level expression of the taaG2 transformed by a gene encoding A. oryzae Taka-amyla- gene.2–4) CreA is a negative regulatory factor with a se A, the major amylase (taaG2), we have found that C2H2-type zinc finger motif that mediates carbon three factors, CCAAT-box binding protein, CreA, and catabolite repression. Analysis with recombinant CreA AmyR, are involved in taaG2 gene expression and protein indicated that four CreA binding sites in the regulation. In this review, the focus is on the CCAAT- taaG2 promoter region are involved in the repression of box binding protein of filamentous fungi. The assembly, taaG2 expression by glucose.1) AmyR is a specific nuclear translocation, and transcriptional enhancement transcriptional activator with a Zn(II)2 Cys6 binuclear mechanisms of the CCAAT-box binding protein are cluster DNA-binding motif. AmyR binds at approxi- discussed. mately À200 in the promoter region of taaG2. The binding site, designated SRE, is required for inducible Key words: Aspergillus; amylase; CCAAT-box; Hap expression.7–13) In this review, I have focused on a wide complex; NF-Y domain regulatory factor, which is a CCAAT-box binding protein in aspergilli. Filamentous fungi are frequently used for the pro- duction of industrial enzymes because they produce a variety of enzymes including polysaccharide-degrading enzymes. They are also effective hosts for the produc- tion of foreign proteins due to their high enzyme secretion capability. Many filamentous fungi produce amylolytic enzymes. Among these, Aspergillus species, such as A. oryzae and A. niger, are known to be good producers. Hence, Aspergillus species are widely used in the Japanese fermentation industry, such as in sake brewing. Starch is a major storage polysaccharide in green plants and is composed of -1,4-glucan chains with -1,6 branches. Aspergillus species produce -amylase, glucoamylases, Fig. 1. Schematic Representation of the Taka-Amylase A Promoter and -glucosidases. These enzymes synergistically Region. degrade starch to produce glucose. -Amylases hydro- Taka-amylase A is a major amylase of A. oryzae. The CCAAT- lyze the -1,4 linkages of amylose, and glucoamylases box binding protein and AmyR bind to the CCAAT-box containing and -glucosidases exolytically hydrolyze the -1,4 region (À313 to À300) and SRE, the starch responsive element (À200 to À178), respectively. The general transcription factors and linkages from the nonreducing ends and release - RNA polymerase II are also shown. CreA, the carbon catabolite glucose and -glucose respectively. repressor, and its binding sites are omitted to avoid complexity. The Regulatory mechanisms that underlie the expression positions of the cis elements in the promoter are arbitrary. To whom correspondence should be addressed. Fax: +81-52-789-4086; E-mail: [email protected] 664 M. KATO I. The CCAAT Sequence and CCAAT Bind- Hap2p, Hap3p, and Hap5p, are necessary for DNA ing Proteins binding, while Hap4p is involved in transcriptional activation.29,32,33) On the other hand, the mammalian The CCAAT sequence is one of the most common CCAAT-box binding factor, NF-Y, is composed of three cis-elements present in the promoter regions of numer- subunits, NF-YA (or CBF-B, corresponding to Hap2p), ous eukaryotic genes. A statistical analysis of over 500 NF-YB (or CBF-A, corresponding to Hap3p), and NF- promoters revealed that the CCAAT sequence is an YC (or CBF-C, corresponding to Hap5p). No Hap4p element present in approximately 30% of eukaryotic homolog has been identified in higher eukaryotes, promoters.14,15) The CCAAT sequence is present in the indicating that three subunits might be sufficient for forward or reverse orientation between À60 and À100 DNA binding and transcriptional activation. Indeed, the of the major transcription start sites. Several DNA N-terminal region of NF-YA and the C-terminal region binding proteins named for their CCAAT sequence of NF-YC were found to be responsible for transcrip- binding have been isolated and characterized: CTF/NF1 tional activation based on assessment by both in vitro (CCAAT Transcription Factor/Nuclear Factor 1);16–19) transcription systems with recombinant proteins and C/EBP (CCAAT/Enhancer Binding Protein);20–25) and transfections of mammalian cells with the LexA and NF-Y/Hap (Nuclear Factor Y/Hem activation pro- GAL4 fusion genes. These activation domains are rich in tein).26–29) Factors in the CTF/NF1 and C/EBP groups glutamine and hydrophobic amino acid residues, and are not genuine CCAAT-box binding proteins because show amino acid sequence similarities to each other and they recognize the palindromic sequences in a manner to the glutamine-rich activation domain of transcription that is different from the widespread consensus derived factor Sp1.34–36) by statistical analysis. On the other hand, promoter compilation and site-selection analysis of the transcrip- II. CCAAT Binding Proteins of Filamentous tion factor of the NF-Y/Hap family revealed the binding Fungi sequence –C G/A G/A C C A A T C/G A/G C A/C–, in agreement with the consensus sequence deduced from The CCAAT sequence in filamentous fungi has been the statistical studies described above.30,31) The factor shown to modulate the expression of several genes, such belonging to the NF-Y/Hap family has been discovered as the A. nidulans acetamidase gene (amdS), the in a variety of organisms. These factors have been A. oryzae Taka-amylase A gene (taa), the A. nidulans designated Hap complex (Saccharomyces cerevisiae, penicillin biosynthesis genes (ipnA and aatA), and the Shizosaccharomyces pombe, Kluveromyces lactis, Ara- Neurospora crassa NADP-specific glutamate dehydro- bidopsis thaliana, and Aspergillus species), CBF, or NF- genase gene (am).13,37) Y(Xenopus and mammals). These factors are summa- In filamentous fungi, the CCAAT-binding proteins, rized in Table 1. The Hap complex in S. cerevisiae was which are homologs of the yeast Hap complex, have also the first factor in this family to be identified as a heme- been characterized:13,37) AnCF (A. nidulans CCAAT- dependent transcriptional activator. This complex re- binding factor) for amdS by Hynes and his colleagues, sponds to two stimuli, heme and nonfermentable energy AnCP (A. nidulans CCAAT-binding protein) for taa by sources, and it comprises four subunits, Hap2p, Hap3p, our group, PENR1 for ipnA and aatA by Brakhage’s Hap4p, and Hap5p. Among the four subunits, three, group, and AAB for am by Kinsey’s group. The hapC Table 1. CCAAT-Box Binding Proteins in the NF-Y/Hap Family Name Subunits Examples of regulated genes References Filamentous fungi Aspergillus species Hap complex HapB/C/E taaG2, amdS, aatA, ipnA, 13, 37 (AnCP, AoCP, gatA, gdhA, fmdS, eglA, AnCF, PenR1) agdA Neurospora crassa AAB1 Hap2/3/5 am 41, 42 Trichoderma reesei Hap complex Hap2/3/5 cbh2, xyn1, xyn2 43, 44 Yeast Saccharomyces cerevisiae Hap complex Hap2/3/4/5 CYC1, CIT1, COX6, HEM1 79 CYT1, LPD1, ASN1, SOD2 Kluveromyces lactis Hap complex Hap2/3/4/5 KlDLD 80 Shizosaccharomyces pombe Hap complex Php2/3/5 CYC1 81 Plant Arabidopsis thaliana Hap complex Hap2/3/5 embryo development genes 82, 86 Amphibian Xenopus laevis NF-Y NF-YA/B/C HSP70 83 Mammal mouse NF-Y NF-YA/B/C MHC II genes, Globin , 79, 84, 85 (CBF) (CBF-A/B/C) Collagen 1(I), Osteopontin, Albmin, PDGF , GPAT, CyclA, E2F1, RRR2, CCAAT-Box Binding Protein in Filamentous Fungi 665 gene, which is a homolog of the hap3 gene of induction of Taka-amylase A, as described in the first S. cerevisiae, has been isolated from A. nidulans by section of this paper. A nuclear protein designated Hynes and his colleagues. Disruption of the hapC gene AnCP, which was renamed the Hap complex, has been resulted in loss of binding of AnCP, AnCF, and PENR1 shown to bind in vitro to the CCAAT sequence in the to the CCAAT sequence, indicating that HapC is a taa promoter.4) This has also been confirmed by DNase I component of AnCP, AnCF, and PENR1.3,38,39) We footprinting analysis and electrophoretic mobility shift further confirmed this result by a supershift assay with assay (EMSA) using the taa promoter DNA as a probe.2) anti-HapC antibody.3) Furthermore, a DNA-complex has By means of EMSA with synthetic oligonucleotide successfully been reconstituted using recombinant HapC probes corresponding to the proximal regions containing together with the recombinant S. cerevisiae Hap2p and the CCAAT sequence of the taa gene, the minimum Hap5p subunits.3) The hapB and hapE genes, which are sequence comprising a 14 base-paired region including homologs of the hap2 and hap5 genes of S.
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