E4RF4_ADE02
ID E4RF4_ADE02 Reviewed; 114 AA.
AC P03240;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 21-JUL-1986, sequence version 1.
DT 29-SEP-2021, entry version 63.
DE RecName: Full=Early 4 ORF4 protein;
DE Short=E4 ORF4;
DE AltName: Full=Early E4 13 kDa protein;
OS Human adenovirus C serotype 2 (HAdV-2) (Human adenovirus 2).
OC Viruses; Varidnaviria; Bamfordvirae; Preplasmiviricota; Tectiliviricetes;
OC Rowavirales; Adenoviridae; Mastadenovirus.
OX NCBI_TaxID=10515;
OH NCBI_TaxID=9606; Homo sapiens (Human).
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=6985482; DOI=10.1093/nar/9.16.4023;
RA Herisse J., Rigolet M., Dupont de Dinechin S., Galibert F.;
RT "Nucleotide sequence of adenovirus 2 DNA fragment encoding for the
RT carboxylic region of the fiber protein and the entire E4 region.";
RL Nucleic Acids Res. 9:4023-4042(1981).
RN [2]
RP INTERACTION WITH HOST PPP2R2A.
RX PubMed=8230475; DOI=10.1128/jvi.67.12.7556-7560.1993;
RA Kleinberger T., Shenk T.;
RT "Adenovirus E4orf4 protein binds to protein phosphatase 2A, and the complex
RT down regulates E1A-enhanced junB transcription.";
RL J. Virol. 67:7556-7560(1993).
RN [3]
RP FUNCTION.
RX PubMed=8648720; DOI=10.1128/jvi.70.6.3844-3851.1996;
RA Bondesson M., Ohman K., Manervik M., Fan S., Akusjarvi G.;
RT "Adenovirus E4 open reading frame 4 protein autoregulates E4 transcription
RT by inhibiting E1A transactivation of the E4 promoter.";
RL J. Virol. 70:3844-3851(1996).
RN [4]
RP FUNCTION.
RX PubMed=9603524; DOI=10.1038/30277;
RA Kanopka A., Muhlemann O., Petersen-Mahrt S., Estmer C., Ohrmalm C.,
RA Akusjarvi G.;
RT "Regulation of adenovirus alternative RNA splicing by dephosphorylation of
RT SR proteins.";
RL Nature 393:185-187(1998).
RN [5]
RP FUNCTION.
RC STRAIN=Human adenovirus C serotype 5;
RX PubMed=9696808; DOI=10.1128/jvi.72.9.7144-7153.1998;
RA Marcellus R.C., Lavoie J.N., Boivin D., Shore G.C., Ketner G.,
RA Branton P.E.;
RT "The early region 4 orf4 protein of human adenovirus type 5 induces p53-
RT independent cell death by apoptosis.";
RL J. Virol. 72:7144-7153(1998).
RN [6]
RP INTERACTION WITH HOST PPP2R5E.
RX PubMed=10949930; DOI=10.1038/sj.onc.1203705;
RA Shtrichman R., Sharf R., Kleinberger T.;
RT "Adenovirus E4orf4 protein interacts with both Balpha and B' subunits of
RT protein phosphatase 2A, but E4orf4-induced apoptosis is mediated only by
RT the interaction with Balpha.";
RL Oncogene 19:3757-3765(2000).
RN [7]
RP INTERACTION WITH HOST SRC, AND SUBCELLULAR LOCATION.
RX PubMed=10973994; DOI=10.1083/jcb.150.5.1037;
RA Lavoie J.N., Champagne C., Gingras M.C., Robert A.;
RT "Adenovirus E4 open reading frame 4-induced apoptosis involves
RT dysregulation of Src family kinases.";
RL J. Cell Biol. 150:1037-1056(2000).
RN [8]
RP INTERACTION WITH HOST PPP2R2A.
RX PubMed=10933694; DOI=10.1128/jvi.74.17.7869-7877.2000;
RA Marcellus R.C., Chan H., Paquette D., Thirlwell S., Boivin D.,
RA Branton P.E.;
RT "Induction of p53-independent apoptosis by the adenovirus E4orf4 protein
RT requires binding to the Balpha subunit of protein phosphatase 2A.";
RL J. Virol. 74:7869-7877(2000).
RN [9]
RP MUTAGENESIS OF TYR-26; TYR-42 AND TYR-62.
RX PubMed=11739721; DOI=10.1128/mcb.22.1.41-56.2002;
RA Gingras M.C., Champagne C., Roy M., Lavoie J.N.;
RT "Cytoplasmic death signal triggered by SRC-mediated phosphorylation of the
RT adenovirus E4orf4 protein.";
RL Mol. Cell. Biol. 22:41-56(2002).
RN [10]
RP INTERACTION WITH HOST SRC.
RX PubMed=15070897; DOI=10.1074/jbc.m400933200;
RA Champagne C., Landry M.C., Gingras M.C., Lavoie J.N.;
RT "Activation of adenovirus type 2 early region 4 ORF4 cytoplasmic death
RT function by direct binding to Src kinase domain.";
RL J. Biol. Chem. 279:25905-25915(2004).
RN [11]
RP SUBCELLULAR LOCATION.
RX PubMed=15334069; DOI=10.1038/sj.onc.1207919;
RA Miron M.J., Gallouzi I.E., Lavoie J.N., Branton P.E.;
RT "Nuclear localization of the adenovirus E4orf4 protein is mediated through
RT an arginine-rich motif and correlates with cell death.";
RL Oncogene 23:7458-7468(2004).
RN [12]
RP INTERACTION WITH HOST PPP2R2A.
RX PubMed=18653458; DOI=10.1128/jvi.00791-08;
RA Ben-Israel H., Sharf R., Rechavi G., Kleinberger T.;
RT "Adenovirus E4orf4 protein downregulates MYC expression through interaction
RT with the PP2A-B55 subunit.";
RL J. Virol. 82:9381-9388(2008).
RN [13]
RP FUNCTION.
RX PubMed=15775987; DOI=10.1038/sj.emboj.7600597;
RA O'Shea C., Klupsch K., Choi S., Bagus B., Soria C., Shen J., McCormick F.,
RA Stokoe D.;
RT "Adenoviral proteins mimic nutrient/growth signals to activate the mTOR
RT pathway for viral replication.";
RL EMBO J. 24:1211-1221(2005).
RN [14]
RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF 66-ARG--ARG-75.
RC STRAIN=Human adenovirus C serotype 5;
RX PubMed=19073741; DOI=10.1128/jvi.01703-08;
RA Miron M.J., Blanchette P., Groitl P., Dallaire F., Teodoro J.G., Li S.,
RA Dobner T., Branton P.E.;
RT "Localization and importance of the adenovirus E4orf4 protein during lytic
RT infection.";
RL J. Virol. 83:1689-1699(2009).
RN [15]
RP INTERACTION WITH HOST BAZ1A/ACF1.
RX PubMed=21546548; DOI=10.1093/nar/gkr231;
RA Brestovitsky A., Sharf R., Mittelman K., Kleinberger T.;
RT "The adenovirus E4orf4 protein targets PP2A to the ACF chromatin-remodeling
RT factor and induces cell death through regulation of SNF2h-containing
RT complexes.";
RL Nucleic Acids Res. 39:6414-6427(2011).
RN [16]
RP REVIEW.
RX PubMed=15769610; DOI=10.2741/1604;
RA Weitzman M.D.;
RT "Functions of the adenovirus E4 proteins and their impact on viral
RT vectors.";
RL Front. Biosci. 10:1106-1117(2005).
RN [17]
RP REVIEW.
RX PubMed=18508565; DOI=10.2741/3059;
RA Akusjarvi G.;
RT "Temporal regulation of adenovirus major late alternative RNA splicing.";
RL Front. Biosci. 13:5006-5015(2008).
CC -!- FUNCTION: Plays a role in viral alternative pre-mRNA splicing.
CC Activates dephosphorylation by protein phosphatase 2A of host SR
CC proteins and converts their splicing properties. When expressed alone
CC ex vivo, induces p53/TP53-independent apoptosis called cytoplasmic
CC death. May mimic nutrient/growth signals to activate the host mTOR
CC pathway. {ECO:0000269|PubMed:15775987, ECO:0000269|PubMed:8648720,
CC ECO:0000269|PubMed:9603524, ECO:0000269|PubMed:9696808}.
CC -!- SUBUNIT: Interacts with host BAZ1A/ACF1, host PPP2R2A/PP2a-B55alpha
CC subunit, and host PPP2R5E/PP2a-B'B56 subunit. May interact with host
CC SRC. {ECO:0000269|PubMed:10933694, ECO:0000269|PubMed:10949930,
CC ECO:0000269|PubMed:10973994, ECO:0000269|PubMed:15070897,
CC ECO:0000269|PubMed:18653458, ECO:0000269|PubMed:21546548,
CC ECO:0000269|PubMed:8230475}.
CC -!- SUBCELLULAR LOCATION: Host nucleus. Host cytoplasm. Note=When expressed
CC alone ex-vivo the majority is found in the nucleus.
CC Tyrosinephosphorylation would promote cytoplasmic localization.
CC -!- PTM: May be phosphorylated by host SRC kinase.
CC -!- SIMILARITY: Belongs to the adenoviridae E4 ORF4 family. {ECO:0000305}.
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DR EMBL; J01917; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR PIR; A03806; Q4ADD2.
DR RefSeq; AP_000193.1; AC_000007.1.
DR Proteomes; UP000008167; Genome.
DR GO; GO:0030430; C:host cell cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0042025; C:host cell nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0006397; P:mRNA processing; IEA:UniProtKB-KW.
DR GO; GO:0008380; P:RNA splicing; IEA:UniProtKB-KW.
DR InterPro; IPR008680; M_adenovirusE4.
DR Pfam; PF05385; Adeno_E4; 1.
PE 1: Evidence at protein level;
KW Apoptosis; Early protein; Host cytoplasm; Host nucleus;
KW Host-virus interaction; mRNA processing; mRNA splicing; Reference proteome.
FT CHAIN 1..114
FT /note="Early 4 ORF4 protein"
FT /id="PRO_0000221773"
FT MOTIF 66..75
FT /note="Nuclear localization signal"
FT MUTAGEN 26
FT /note="Y->F: Partial loss of phosphorylation ex vivo."
FT /evidence="ECO:0000269|PubMed:11739721"
FT MUTAGEN 42
FT /note="Y->F: Partial loss of phosphorylation ex vivo."
FT /evidence="ECO:0000269|PubMed:11739721"
FT MUTAGEN 62
FT /note="Y->F: Partial loss of phosphorylation ex vivo."
FT /evidence="ECO:0000269|PubMed:11739721"
FT MUTAGEN 66..75
FT /note="RAKRRDRRRR->KAKKKDKKKK: Partial loss of nuclear and
FT nucleolar localization."
FT /evidence="ECO:0000269|PubMed:19073741"
FT MUTAGEN 66..73
FT /note="RAKRRDRR->KAKKKDKK: Partial loss of nuclear and
FT nucleolar localization."
FT MUTAGEN 66..70
FT /note="RAKRR->AAAA: Complete loss of nuclear and nucleolar
FT localization."
FT MUTAGEN 66..70
FT /note="RAKRR->KAKKK: Partial loss of nuclear and nucleolar
FT localization."
FT MUTAGEN 66
FT /note="R->K: Partial loss of nuclear and nucleolar
FT localization."
FT MUTAGEN 69..70
FT /note="RR->AA: Complete loss of nuclear and nucleolar
FT localization."
FT MUTAGEN 72..75
FT /note="RRRR->AAAA: Complete loss of nuclear and nucleolar
FT localization."
FT MUTAGEN 73..75
FT /note="RRR->AAA: Complete loss of nuclear and nucleolar
FT localization."
FT MUTAGEN 74..75
FT /note="RR->AA: Complete loss of nuclear and nucleolar
FT localization."
SQ SEQUENCE 114 AA; 13321 MW; 72FB72749D563457 CRC64;
MVLPALPAPP VCDSQNECVG WLGVAYSAVV DVIRAAAHEG VYIEPEARGR LDALREWIYY
NYYTERAKRR DRRRRSVCHA RTWFCFRKYD YVRRSIWHDT TTNTISVVSA HSVQ
