UPC2_CANAL
ID UPC2_CANAL Reviewed; 712 AA.
AC Q59QC7; A0A1D8PEC3;
DT 01-APR-2015, integrated into UniProtKB/Swiss-Prot.
DT 26-APR-2005, sequence version 1.
DT 25-MAY-2022, entry version 111.
DE RecName: Full=Sterol uptake control protein 2;
GN Name=UPC2 {ECO:0000303|PubMed:15590814}; Synonyms=ECM22;
GN OrderedLocusNames=CAALFM_C108460CA; ORFNames=CaO19.391, CaO19.8021;
OS Candida albicans (strain SC5314 / ATCC MYA-2876) (Yeast).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Saccharomycotina; Saccharomycetes;
OC Saccharomycetales; Debaryomycetaceae; Candida/Lodderomyces clade; Candida.
OX NCBI_TaxID=237561;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=SC5314 / ATCC MYA-2876;
RX PubMed=15123810; DOI=10.1073/pnas.0401648101;
RA Jones T., Federspiel N.A., Chibana H., Dungan J., Kalman S., Magee B.B.,
RA Newport G., Thorstenson Y.R., Agabian N., Magee P.T., Davis R.W.,
RA Scherer S.;
RT "The diploid genome sequence of Candida albicans.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:7329-7334(2004).
RN [2]
RP GENOME REANNOTATION.
RC STRAIN=SC5314 / ATCC MYA-2876;
RX PubMed=17419877; DOI=10.1186/gb-2007-8-4-r52;
RA van het Hoog M., Rast T.J., Martchenko M., Grindle S., Dignard D.,
RA Hogues H., Cuomo C., Berriman M., Scherer S., Magee B.B., Whiteway M.,
RA Chibana H., Nantel A., Magee P.T.;
RT "Assembly of the Candida albicans genome into sixteen supercontigs aligned
RT on the eight chromosomes.";
RL Genome Biol. 8:RESEARCH52.1-RESEARCH52.12(2007).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND GENOME REANNOTATION.
RC STRAIN=SC5314 / ATCC MYA-2876;
RX PubMed=24025428; DOI=10.1186/gb-2013-14-9-r97;
RA Muzzey D., Schwartz K., Weissman J.S., Sherlock G.;
RT "Assembly of a phased diploid Candida albicans genome facilitates allele-
RT specific measurements and provides a simple model for repeat and indel
RT structure.";
RL Genome Biol. 14:RESEARCH97.1-RESEARCH97.14(2013).
RN [4]
RP DISRUPTION PHENOTYPE, AND FUNCTION.
RX PubMed=15590814; DOI=10.1128/ec.3.6.1391-1397.2004;
RA Silver P.M., Oliver B.G., White T.C.;
RT "Role of Candida albicans transcription factor Upc2p in drug resistance and
RT sterol metabolism.";
RL Eukaryot. Cell 3:1391-1397(2004).
RN [5]
RP DISRUPTION PHENOTYPE, FUNCTION, AND DNA-BINDING.
RX PubMed=15855491; DOI=10.1128/aac.49.5.1745-1752.2005;
RA MacPherson S., Akache B., Weber S., De Deken X., Raymond M., Turcotte B.;
RT "Candida albicans zinc cluster protein Upc2p confers resistance to
RT antifungal drugs and is an activator of ergosterol biosynthetic genes.";
RL Antimicrob. Agents Chemother. 49:1745-1752(2005).
RN [6]
RP INDUCTION.
RX PubMed=16039996; DOI=10.1016/j.bbrc.2005.07.018;
RA Singh V., Sinha I., Sadhale P.P.;
RT "Global analysis of altered gene expression during morphogenesis of Candida
RT albicans in vitro.";
RL Biochem. Biophys. Res. Commun. 334:1149-1158(2005).
RN [7]
RP IDENTIFICATION.
RX PubMed=18629206; DOI=10.1002/cfg.492;
RA Maicas S., Moreno I., Nieto A., Gomez M., Sentandreu R., Valentin E.;
RT "In silico analysis for transcription factors with Zn(II)(2)C(6) binuclear
RT cluster DNA-binding domains in Candida albicans.";
RL Comp. Funct. Genomics 6:345-356(2005).
RN [8]
RP INDUCTION.
RX PubMed=15820985; DOI=10.1093/jac/dki088;
RA Copping V.M.S., Barelle C.J., Hube B., Gow N.A.R., Brown A.J.P., Odds F.C.;
RT "Exposure of Candida albicans to antifungal agents affects expression of
RT SAP2 and SAP9 secreted proteinase genes.";
RL J. Antimicrob. Chemother. 55:645-654(2005).
RN [9]
RP FUNCTION, AND MUTAGENESIS OF GLY-648.
RX PubMed=18487346; DOI=10.1128/ec.00103-08;
RA Dunkel N., Liu T.T., Barker K.S., Homayouni R., Morschhauser J.,
RA Rogers P.D.;
RT "A gain-of-function mutation in the transcription factor Upc2p causes
RT upregulation of ergosterol biosynthesis genes and increased fluconazole
RT resistance in a clinical Candida albicans isolate.";
RL Eukaryot. Cell 7:1180-1190(2008).
RN [10]
RP INDUCTION.
RX PubMed=18757808; DOI=10.1099/mic.0.2008/017475-0;
RA Hoot S.J., Oliver B.G., White T.C.;
RT "Candida albicans UPC2 is transcriptionally induced in response to
RT antifungal drugs and anaerobicity through Upc2p-dependent and -independent
RT mechanisms.";
RL Microbiology 154:2748-2756(2008).
RN [11]
RP FUNCTION, AND MUTAGENESIS OF ALA-643.
RX PubMed=19884367; DOI=10.1128/aac.01102-09;
RA Heilmann C.J., Schneider S., Barker K.S., Rogers P.D., Morschhaeuser J.;
RT "An A643T mutation in the transcription factor Upc2p causes constitutive
RT ERG11 upregulation and increased fluconazole resistance in Candida
RT albicans.";
RL Antimicrob. Agents Chemother. 54:353-359(2010).
RN [12]
RP INDUCTION, AND FUNCTION.
RX PubMed=20656915; DOI=10.1128/ec.00130-10;
RA Hoot S.J., Brown R.P., Oliver B.G., White T.C.;
RT "The UPC2 promoter in Candida albicans contains two cis-acting elements
RT that bind directly to Upc2p, resulting in transcriptional autoregulation.";
RL Eukaryot. Cell 9:1354-1362(2010).
RN [13]
RP FUNCTION, AND MUTAGENESIS OF ALA-643.
RX PubMed=21078937; DOI=10.1128/aac.00995-10;
RA Hoot S.J., Smith A.R., Brown R.P., White T.C.;
RT "An A643V amino acid substitution in Upc2p contributes to azole resistance
RT in well-characterized clinical isolates of Candida albicans.";
RL Antimicrob. Agents Chemother. 55:940-942(2011).
RN [14]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=22006003; DOI=10.1128/aac.00574-11;
RA Dhamgaye S., Devaux F., Manoharlal R., Vandeputte P., Shah A.H., Singh A.,
RA Blugeon C., Sanglard D., Prasad R.;
RT "In vitro effect of malachite green on Candida albicans involves multiple
RT pathways and transcriptional regulators UPC2 and STP2.";
RL Antimicrob. Agents Chemother. 56:495-506(2012).
RN [15]
RP FUNCTION, AND MUTAGENESIS OF TRP-478; TYR-642; ALA-643; ALA-646 AND
RP GLY-648.
RX PubMed=22923048; DOI=10.1128/ec.00215-12;
RA Flowers S.A., Barker K.S., Berkow E.L., Toner G., Chadwick S.G.,
RA Gygax S.E., Morschhauser J., Rogers P.D.;
RT "Gain-of-function mutations in UPC2 are a frequent cause of ERG11
RT upregulation in azole-resistant clinical isolates of Candida albicans.";
RL Eukaryot. Cell 11:1289-1299(2012).
RN [16]
RP FUNCTION.
RX PubMed=25385116; DOI=10.1128/aac.04448-14;
RA Schneider S., Morschhaeuser J.;
RT "Induction of Candida albicans drug resistance genes by hybrid zinc cluster
RT transcription factors.";
RL Antimicrob. Agents Chemother. 59:558-569(2015).
RN [17]
RP FUNCTION, DNA-BINDING, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=24145546; DOI=10.1128/aac.01677-13;
RA Gallo-Ebert C., Donigan M., Stroke I.L., Swanson R.N., Manners M.T.,
RA Francisco J., Toner G., Gallagher D., Huang C.Y., Gygax S.E., Webb M.,
RA Nickels J.T. Jr.;
RT "Novel antifungal drug discovery based on targeting pathways regulating the
RT fungus-conserved Upc2 transcription factor.";
RL Antimicrob. Agents Chemother. 58:258-266(2014).
RN [18]
RP FUNCTION.
RX PubMed=24243794; DOI=10.1128/ec.00245-13;
RA Lohberger A., Coste A.T., Sanglard D.;
RT "Distinct roles of Candida albicans drug resistance transcription factors
RT TAC1, MRR1, and UPC2 in virulence.";
RL Eukaryot. Cell 13:127-142(2014).
RN [19]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=24376002; DOI=10.1128/ec.00336-13;
RA Wellington M., Koselny K., Sutterwala F.S., Krysan D.J.;
RT "Candida albicans triggers NLRP3-mediated pyroptosis in macrophages.";
RL Eukaryot. Cell 13:329-340(2014).
RN [20]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=24659578; DOI=10.1128/ec.00221-13;
RA Vasicek E.M., Berkow E.L., Flowers S.A., Barker K.S., Rogers P.D.;
RT "UPC2 is universally essential for azole antifungal resistance in Candida
RT albicans.";
RL Eukaryot. Cell 13:933-946(2014).
RN [21]
RP FUNCTION.
RX PubMed=25084864; DOI=10.1128/ec.00096-14;
RA Van Hauwenhuyse F., Fiori A., Van Dijck P.;
RT "Ascorbic acid inhibition of Candida albicans Hsp90-mediated morphogenesis
RT occurs via the transcriptional regulator Upc2.";
RL Eukaryot. Cell 13:1278-1289(2014).
CC -!- FUNCTION: Transcription factor involved in the regulation of ergosterol
CC biosynthetic genes such as ERG2 and ERG11 through direct binding to
CC sterol response elements (SREs) in the promoters. Binds also to its own
CC promoter on 2 cis-acting elements to promote autoregulation. Regulates
CC sterol uptake across the plasma membrane. Acts as a major regulator of
CC ascorbic acid-induced response. Plays a role in the triggering of
CC pyroptosis, an inflammasome-mediated programmed cell death pathway in
CC macrophages, allowing macrophages escaping.
CC {ECO:0000269|PubMed:15590814, ECO:0000269|PubMed:15855491,
CC ECO:0000269|PubMed:18487346, ECO:0000269|PubMed:19884367,
CC ECO:0000269|PubMed:20656915, ECO:0000269|PubMed:21078937,
CC ECO:0000269|PubMed:22006003, ECO:0000269|PubMed:22923048,
CC ECO:0000269|PubMed:24145546, ECO:0000269|PubMed:24243794,
CC ECO:0000269|PubMed:24376002, ECO:0000269|PubMed:24659578,
CC ECO:0000269|PubMed:25084864, ECO:0000269|PubMed:25385116}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=50 nM for DNA sterol response element (SRE)
CC {ECO:0000269|PubMed:24145546};
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00227}.
CC -!- INDUCTION: Expression is up-regulated by ergosterol depletion, by
CC azoles, and in anaerobic conditions. Transcript is repressed during co-
CC incubated with macrophages, a condition that induces filamentous
CC growth. Promotes positive auto-regulation through binding to its own
CC promoter. {ECO:0000269|PubMed:15820985, ECO:0000269|PubMed:16039996,
CC ECO:0000269|PubMed:18757808, ECO:0000269|PubMed:20656915}.
CC -!- DISRUPTION PHENOTYPE: Shows increased susceptibility to the azole drugs
CC ketoconazole, itraconazole, and fluconazole; drugs that act on
CC ergosterol biosynthesis such as terbinafine, fenpropimorph, and
CC lovastatin; as well as malachite green. Leads to lower ergosterol
CC levels. Decreases pyroptosis but has little effect on filamentation in
CC the macrophage. {ECO:0000269|PubMed:15590814,
CC ECO:0000269|PubMed:15855491, ECO:0000269|PubMed:22006003,
CC ECO:0000269|PubMed:24376002, ECO:0000269|PubMed:24659578}.
CC -!- MISCELLANEOUS: Gain-of-function mutations in UPC2 are more prevalent
CC among clinical isolates than previously thought and make a significant
CC contribution to azole antifungal resistance.
CC {ECO:0000269|PubMed:22923048}.
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DR EMBL; CP017623; AOW26484.1; -; Genomic_DNA.
DR RefSeq; XP_711879.1; XM_706786.2.
DR AlphaFoldDB; Q59QC7; -.
DR SMR; Q59QC7; -.
DR STRING; 237561.Q59QC7; -.
DR PRIDE; Q59QC7; -.
DR EnsemblFungi; KHC83595; KHC83595; W5Q_00814.
DR EnsemblFungi; KHC89031; KHC89031; I503_00822.
DR GeneID; 3646489; -.
DR KEGG; cal:CAALFM_C108460CA; -.
DR CGD; CAL0000191743; UPC2.
DR VEuPathDB; FungiDB:C1_08460C_A; -.
DR eggNOG; ENOG502QRM1; Eukaryota.
DR HOGENOM; CLU_011669_0_0_1; -.
DR InParanoid; Q59QC7; -.
DR OMA; SFTTEMK; -.
DR OrthoDB; 872957at2759; -.
DR SABIO-RK; Q59QC7; -.
DR PRO; PR:Q59QC7; -.
DR Proteomes; UP000000559; Chromosome 1.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0003677; F:DNA binding; IEA:UniProtKB-KW.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IDA:CGD.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0008204; P:ergosterol metabolic process; IMP:CGD.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IMP:CGD.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:CGD.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0016125; P:sterol metabolic process; IMP:CGD.
DR CDD; cd00067; GAL4; 1.
DR Gene3D; 4.10.240.10; -; 1.
DR InterPro; IPR021858; Fun_TF.
DR InterPro; IPR001138; Zn2-C6_fun-type_DNA-bd.
DR InterPro; IPR036864; Zn2-C6_fun-type_DNA-bd_sf.
DR Pfam; PF11951; Fungal_trans_2; 1.
DR Pfam; PF00172; Zn_clus; 1.
DR SMART; SM00066; GAL4; 1.
DR SUPFAM; SSF57701; SSF57701; 1.
DR PROSITE; PS00463; ZN2_CY6_FUNGAL_1; 1.
DR PROSITE; PS50048; ZN2_CY6_FUNGAL_2; 1.
PE 1: Evidence at protein level;
KW Activator; DNA-binding; Metal-binding; Nucleus; Reference proteome;
KW Transcription; Transcription regulation; Virulence; Zinc.
FT CHAIN 1..712
FT /note="Sterol uptake control protein 2"
FT /id="PRO_0000431801"
FT DNA_BIND 54..81
FT /note="Zn(2)-C6 fungal-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00227"
FT REGION 1..52
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 95..150
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 236..342
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1..36
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 100..115
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 116..150
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MUTAGEN 478
FT /note="W->C: Leads to increased ERG11 expression, increased
FT cellular ergosterol, and decreased susceptibility to
FT fluconazole."
FT /evidence="ECO:0000269|PubMed:22923048"
FT MUTAGEN 642
FT /note="Y->F: Leads to increased ERG11 expression, increased
FT cellular ergosterol, and decreased susceptibility to
FT fluconazole."
FT /evidence="ECO:0000269|PubMed:22923048"
FT MUTAGEN 643
FT /note="A->T,V: Leads to increased ERG11 expression,
FT increased cellular ergosterol, and decreased susceptibility
FT to fluconazole."
FT /evidence="ECO:0000269|PubMed:22923048"
FT MUTAGEN 646
FT /note="A->V: Leads to increased ERG11 expression, increased
FT cellular ergosterol, and decreased susceptibility to
FT fluconazole."
FT /evidence="ECO:0000269|PubMed:22923048"
FT MUTAGEN 648
FT /note="G->D,S: Leads to increased ERG11 expression,
FT increased cellular ergosterol, and decreased susceptibility
FT to fluconazole."
FT /evidence="ECO:0000269|PubMed:22923048"
SQ SEQUENCE 712 AA; 77035 MW; F6AED0926B01AF61 CRC64;
MMMTVKQESP NSTLNTSEFS SDENLKTNNS EPPKKVSKSS TGKRKYHQKS RNGCSTCKKR
RVKCDEQRPV CGNCTKLKLD CGYLHEPLEN ILNTKKDIAN NEPPSKKRKR KVSTVSAASD
SESTTQQATP SLTPSPNHSQ DIKTQPVIPP TNPLSALSSG LLSAGNLNNL NVAHLVNNLS
GLGDLSNLAS LGNLASLSNL ASLAQLPIDL SNLGSLLDSP AASNIAASFL GSAAATTVPP
TTNSEFKESN QRKSQTQMPP QPTVPITSMG AATTTSSHQQ ANMPSRSKPQ PETLQSSIPA
TTSGSPGMSY PGCPSNSDPF GRSSDKSLPN ISPNMSIPAN PLSDPLTQGM RSNLNMLDLK
LMFHYTSVVA NTITGAGISD TNIWNCDIPK LAFEHPFLMH SILAFSATHL SRTEKGLDQC
VTCHRGDALR LLREAVLNIN ADNTDALVAS ALILIMDSLA NASFPSSTSP KSLPASAWIF
HVKGAATILT AVWPLTEASR FYKFISVDLG DLGDIINQGV NMNKSKGIDR ENSAYYTDLE
CHDADIADLF PVLLDSPYLI TLAYLNKLHK ERYKSDFILR IFAFPALLDK QFMGLLMSGD
VKAMRIMRSY YKLLRSFTTE MKDKVWFLEG VSQVLPVNVE EYAGGAGGMH MMMDFLGGGP
AIVDDNEIDA EITKFDPSGT LTNKLIDTDN LPSVLTSNLD LMQGDNGFMN MK
