ID   IRF8_HUMAN              Reviewed;         426 AA.
AC   Q02556; A0AV82;
DT   01-JUL-1993, integrated into UniProtKB/Swiss-Prot.
DT   15-JUL-1999, sequence version 2.
DT   27-MAR-2024, entry version 198.
DE   RecName: Full=Interferon regulatory factor 8 {ECO:0000305};
DE            Short=IRF-8;
DE   AltName: Full=Interferon consensus sequence-binding protein {ECO:0000303|PubMed:1460054};
DE            Short=H-ICSBP {ECO:0000303|PubMed:1460054};
DE            Short=ICSBP {ECO:0000303|PubMed:1460054};
GN   Name=IRF8 {ECO:0000303|PubMed:21524210, ECO:0000312|HGNC:HGNC:5358};
GN   Synonyms=ICSBP1 {ECO:0000303|PubMed:1460054};
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND INDUCTION BY IFNG.
RC   TISSUE=Lung, and Monocyte;
RX   PubMed=1460054; DOI=10.1016/s0021-9258(19)74081-2;
RA   Weisz A., Marx P., Sharf R., Appella E., Driggers P.H., Ozato K.,
RA   Levi B.-Z.;
RT   "Human interferon consensus sequence binding protein is a negative
RT   regulator of enhancer elements common to interferon-inducible genes.";
RL   J. Biol. Chem. 267:25589-25596(1992).
RN   [2]
RP   SEQUENCE REVISION.
RA   Schmidt M.;
RL   Submitted (JUL-1997) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Brain;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [4]
RP   INTERACTION WITH COPS2.
RX   PubMed=10991940; DOI=10.1074/jbc.m004900200;
RA   Cohen H., Azriel A., Cohen T., Meraro D., Hashmueli S., Bech-Otschir D.,
RA   Kraft R., Dubiel W., Levi B.Z.;
RT   "Interaction between interferon consensus sequence-binding protein and
RT   COP9/signalosome subunit CSN2 (Trip15). A possible link between interferon
RT   regulatory factor signaling and the COP9/signalosome.";
RL   J. Biol. Chem. 275:39081-39089(2000).
RN   [5]
RP   INDUCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX   PubMed=23166356; DOI=10.1084/jem.20121387;
RA   Basso K., Schneider C., Shen Q., Holmes A.B., Setty M., Leslie C.,
RA   Dalla-Favera R.;
RT   "BCL6 positively regulates AID and germinal center gene expression via
RT   repression of miR-155.";
RL   J. Exp. Med. 209:2455-2465(2012).
RN   [6]
RP   VARIANTS [LARGE SCALE ANALYSIS] LYS-81 AND THR-197.
RX   PubMed=16959974; DOI=10.1126/science.1133427;
RA   Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA   Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA   Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA   Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA   Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA   Velculescu V.E.;
RT   "The consensus coding sequences of human breast and colorectal cancers.";
RL   Science 314:268-274(2006).
RN   [7]
RP   VARIANT IMD32A ALA-80, VARIANT IMD32B GLU-108, CHARACTERIZATION OF VARIANT
RP   IMD32A ALA-80, CHARACTERIZATION OF VARIANT IMD32B GLU-108, INVOLVEMENT IN
RP   IMD32A, AND INVOLVEMENT IN IMD32B.
RX   PubMed=21524210; DOI=10.1056/nejmoa1100066;
RA   Hambleton S., Salem S., Bustamante J., Bigley V., Boisson-Dupuis S.,
RA   Azevedo J., Fortin A., Haniffa M., Ceron-Gutierrez L., Bacon C.M.,
RA   Menon G., Trouillet C., McDonald D., Carey P., Ginhoux F., Alsina L.,
RA   Zumwalt T.J., Kong X.F., Kumararatne D., Butler K., Hubeau M., Feinberg J.,
RA   Al-Muhsen S., Cant A., Abel L., Chaussabel D., Doffinger R., Talesnik E.,
RA   Grumach A., Duarte A., Abarca K., Moraes-Vasconcelos D., Burk D.,
RA   Berghuis A., Geissmann F., Collin M., Casanova J.L., Gros P.;
RT   "IRF8 mutations and human dendritic-cell immunodeficiency.";
RL   N. Engl. J. Med. 365:127-138(2011).
RN   [8]
RP   CHARACTERIZATION OF VARIANT IMD32B GLU-108, FUNCTION, SUBCELLULAR LOCATION,
RP   UBIQUITINATION, DESUMOYLATION, AND MUTAGENESIS OF LYS-108.
RX   PubMed=25122610; DOI=10.1182/blood-2014-04-570879;
RA   Salem S., Langlais D., Lefebvre F., Bourque G., Bigley V., Haniffa M.,
RA   Casanova J.L., Burk D., Berghuis A., Butler K.M., Leahy T.R., Hambleton S.,
RA   Gros P.;
RT   "Functional characterization of the human dendritic cell immunodeficiency
RT   associated with the IRF8(K108E) mutation.";
RL   Blood 124:1894-1904(2014).
RN   [9]
RP   FUNCTION.
RX   PubMed=29434592; DOI=10.3389/fimmu.2018.00062;
RA   Agod Z., Pazmandi K., Bencze D., Vereb G., Biro T., Szabo A.,
RA   Rajnavolgyi E., Bacsi A., Engel P., Lanyi A.;
RT   "Signaling lymphocyte activation molecule family 5 enhances autophagy and
RT   fine-tunes cytokine response in monocyte-derived dendritic cells via
RT   stabilization of interferon regulatory factor 8.";
RL   Front. Immunol. 9:62-62(2018).
RN   [10]
RP   INTERACTION WITH SPI1.
RX   PubMed=33951726; DOI=10.1084/jem.20201750;
RA   Le Coz C., Nguyen D.N., Su C., Nolan B.E., Albrecht A.V., Xhani S., Sun D.,
RA   Demaree B., Pillarisetti P., Khanna C., Wright F., Chen P.A., Yoon S.,
RA   Stiegler A.L., Maurer K., Garifallou J.P., Rymaszewski A., Kroft S.H.,
RA   Olson T.S., Seif A.E., Wertheim G., Grant S.F.A., Vo L.T., Puck J.M.,
RA   Sullivan K.E., Routes J.M., Zakharova V., Shcherbina A., Mukhina A.,
RA   Rudy N.L., Hurst A.C.E., Atkinson T.P., Boggon T.J., Hakonarson H.,
RA   Abate A.R., Hajjar J., Nicholas S.K., Lupski J.R., Verbsky J., Chinn I.K.,
RA   Gonzalez M.V., Wells A.D., Marson A., Poon G.M.K., Romberg N.;
RT   "Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia
RT   patients.";
RL   J. Exp. Med. 218:0-0(2021).
CC   -!- FUNCTION: Transcription factor that specifically binds to the upstream
CC       regulatory region of type I interferon (IFN) and IFN-inducible MHC
CC       class I genes (the interferon consensus sequence (ICS))
CC       (PubMed:25122610). Can both act as a transcriptional activator or
CC       repressor (By similarity). Plays a negative regulatory role in cells of
CC       the immune system (By similarity). Involved in CD8(+) dendritic cell
CC       differentiation by forming a complex with the BATF-JUNB heterodimer in
CC       immune cells, leading to recognition of AICE sequence (5'-TGAnTCA/GAAA-
CC       3'), an immune-specific regulatory element, followed by cooperative
CC       binding of BATF and IRF8 and activation of genes (By similarity).
CC       Required for the development of plasmacytoid dendritic cells (pDCs),
CC       which produce most of the type I IFN in response to viral infection (By
CC       similarity). Positively regulates macroautophagy in dendritic cells
CC       (PubMed:29434592). Acts as a transcriptional repressor of osteoclast
CC       differentiation factors such as NFATC1 and EEIG1 (By similarity).
CC       {ECO:0000250|UniProtKB:P23611, ECO:0000269|PubMed:25122610,
CC       ECO:0000269|PubMed:29434592}.
CC   -!- SUBUNIT: Interacts (via C-terminus) with TRIM21 (via C-terminus).
CC       Interacts with the BATF-JUNB heterodimer. Interacts with BATF (via bZIP
CC       domain); the interaction is direct (By similarity). Interacts with
CC       COPS2. Interacts with SPI1 (PubMed:33951726). {ECO:0000250,
CC       ECO:0000269|PubMed:10991940, ECO:0000269|PubMed:33951726}.
CC   -!- INTERACTION:
CC       Q02556; O14896: IRF6; NbExp=3; IntAct=EBI-2866563, EBI-6115643;
CC       Q02556; Q96CV9: OPTN; NbExp=3; IntAct=EBI-2866563, EBI-748974;
CC   -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:23166356,
CC       ECO:0000269|PubMed:25122610}. Cytoplasm {ECO:0000269|PubMed:25122610}.
CC       Note=In resting macrophages, localizes in the cytoplasm. Translocated
CC       in the nucleus upon IFN-gamma induction. {ECO:0000269|PubMed:25122610}.
CC   -!- TISSUE SPECIFICITY: Predominantly expressed in lymphoid tissues.
CC       {ECO:0000269|PubMed:1460054, ECO:0000269|PubMed:23166356}.
CC   -!- INDUCTION: By IFNG/IFN-gamma. Negatively regulated by microRNA-155
CC       (miR155). {ECO:0000269|PubMed:1460054, ECO:0000269|PubMed:23166356}.
CC   -!- PTM: Ubiquitinated (PubMed:25122610). Ubiquitination by TRIM21 in
CC       macrophages, a process that is strongly increased upon interferon gamma
CC       stimulation, leds to the enhanced transcriptional activity of target
CC       cytokine genes (By similarity). Ubiquitination leads to its degradation
CC       by the proteasome (PubMed:25122610). {ECO:0000250,
CC       ECO:0000269|PubMed:25122610}.
CC   -!- PTM: Sumoylated with SUMO3. Desumoylated by SENP1.
CC       {ECO:0000269|PubMed:25122610}.
CC   -!- DISEASE: Immunodeficiency 32A (IMD32A) [MIM:614893]: An immunologic
CC       disorder characterized by abnormal peripheral blood myeloid phenotype
CC       with a marked loss of CD11C-positive/CD1C dendritic cells, resulting in
CC       selective susceptibility to mycobacterial infections.
CC       {ECO:0000269|PubMed:21524210}. Note=The disease is caused by variants
CC       affecting the gene represented in this entry.
CC   -!- DISEASE: Immunodeficiency 32B (IMD32B) [MIM:226990]: An autosomal
CC       recessive primary immunodeficiency characterized by monocyte and
CC       dendritic cell deficiency, myeloproliferation, and susceptibility to
CC       severe opportunistic infections, including disseminated BCG infection
CC       and oral candidiasis. {ECO:0000269|PubMed:21524210,
CC       ECO:0000269|PubMed:25122610}. Note=The disease is caused by variants
CC       affecting the gene represented in this entry.
CC   -!- SIMILARITY: Belongs to the IRF family. {ECO:0000255|PROSITE-
CC       ProRule:PRU00840}.
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DR   EMBL; M91196; AAB63813.1; -; mRNA.
DR   EMBL; BC126247; AAI26248.1; -; mRNA.
DR   CCDS; CCDS10956.1; -.
DR   PIR; A45064; A45064.
DR   RefSeq; NP_002154.1; NM_002163.2.
DR   AlphaFoldDB; Q02556; -.
DR   SMR; Q02556; -.
DR   BioGRID; 109621; 54.
DR   IntAct; Q02556; 41.
DR   STRING; 9606.ENSP00000268638; -.
DR   iPTMnet; Q02556; -.
DR   PhosphoSitePlus; Q02556; -.
DR   BioMuta; IRF8; -.
DR   DMDM; 6016308; -.
DR   jPOST; Q02556; -.
DR   MassIVE; Q02556; -.
DR   MaxQB; Q02556; -.
DR   PaxDb; 9606-ENSP00000268638; -.
DR   PeptideAtlas; Q02556; -.
DR   ProteomicsDB; 58110; -.
DR   Antibodypedia; 1058; 508 antibodies from 42 providers.
DR   DNASU; 3394; -.
DR   Ensembl; ENST00000268638.10; ENSP00000268638.4; ENSG00000140968.12.
DR   Ensembl; ENST00000564803.6; ENSP00000456992.2; ENSG00000140968.12.
DR   Ensembl; ENST00000696887.1; ENSP00000512953.1; ENSG00000140968.12.
DR   GeneID; 3394; -.
DR   KEGG; hsa:3394; -.
DR   MANE-Select; ENST00000268638.10; ENSP00000268638.4; NM_002163.4; NP_002154.1.
DR   UCSC; uc002fjh.4; human.
DR   AGR; HGNC:5358; -.
DR   CTD; 3394; -.
DR   DisGeNET; 3394; -.
DR   GeneCards; IRF8; -.
DR   HGNC; HGNC:5358; IRF8.
DR   HPA; ENSG00000140968; Tissue enhanced (lymphoid).
DR   MalaCards; IRF8; -.
DR   MIM; 226990; phenotype.
DR   MIM; 601565; gene.
DR   MIM; 614893; phenotype.
DR   neXtProt; NX_Q02556; -.
DR   OpenTargets; ENSG00000140968; -.
DR   Orphanet; 319600; Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency.
DR   PharmGKB; PA29606; -.
DR   VEuPathDB; HostDB:ENSG00000140968; -.
DR   eggNOG; ENOG502QT9P; Eukaryota.
DR   GeneTree; ENSGT00940000158140; -.
DR   InParanoid; Q02556; -.
DR   OMA; SSYEQYH; -.
DR   OrthoDB; 3740806at2759; -.
DR   PhylomeDB; Q02556; -.
DR   TreeFam; TF328512; -.
DR   PathwayCommons; Q02556; -.
DR   Reactome; R-HSA-877300; Interferon gamma signaling.
DR   Reactome; R-HSA-909733; Interferon alpha/beta signaling.
DR   SignaLink; Q02556; -.
DR   SIGNOR; Q02556; -.
DR   BioGRID-ORCS; 3394; 41 hits in 1181 CRISPR screens.
DR   ChiTaRS; IRF8; human.
DR   GeneWiki; IRF8; -.
DR   GenomeRNAi; 3394; -.
DR   Pharos; Q02556; Tbio.
DR   PRO; PR:Q02556; -.
DR   Proteomes; UP000005640; Chromosome 16.
DR   RNAct; Q02556; Protein.
DR   Bgee; ENSG00000140968; Expressed in monocyte and 188 other cell types or tissues.
DR   ExpressionAtlas; Q02556; baseline and differential.
DR   GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR   GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR   GO; GO:0005829; C:cytosol; TAS:Reactome.
DR   GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR   GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR   GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB.
DR   GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IDA:NTNU_SB.
DR   GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:NTNU_SB.
DR   GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL.
DR   GO; GO:0006914; P:autophagy; IEA:UniProtKB-KW.
DR   GO; GO:0071222; P:cellular response to lipopolysaccharide; IEA:Ensembl.
DR   GO; GO:0071346; P:cellular response to type II interferon; IDA:UniProtKB.
DR   GO; GO:0042742; P:defense response to bacterium; IEA:Ensembl.
DR   GO; GO:0042832; P:defense response to protozoan; IEA:Ensembl.
DR   GO; GO:0097028; P:dendritic cell differentiation; ISS:UniProtKB.
DR   GO; GO:0002316; P:follicular B cell differentiation; IEA:Ensembl.
DR   GO; GO:0002314; P:germinal center B cell differentiation; IEA:Ensembl.
DR   GO; GO:0006955; P:immune response; TAS:ProtInc.
DR   GO; GO:0002376; P:immune system process; IBA:GO_Central.
DR   GO; GO:0030099; P:myeloid cell differentiation; IEA:Ensembl.
DR   GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR   GO; GO:0006909; P:phagocytosis; IEA:Ensembl.
DR   GO; GO:0002273; P:plasmacytoid dendritic cell differentiation; ISS:UniProtKB.
DR   GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl.
DR   GO; GO:0032735; P:positive regulation of interleukin-12 production; IEA:Ensembl.
DR   GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR   GO; GO:0032729; P:positive regulation of type II interferon production; IEA:Ensembl.
DR   GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR   GO; GO:0032479; P:regulation of type I interferon production; ISS:UniProtKB.
DR   CDD; cd00103; IRF; 1.
DR   Gene3D; 2.60.200.10; -; 1.
DR   Gene3D; 1.10.10.10; Winged helix-like DNA-binding domain superfamily/Winged helix DNA-binding domain; 1.
DR   InterPro; IPR019817; Interferon_reg_fac_CS.
DR   InterPro; IPR001346; Interferon_reg_fact_DNA-bd_dom.
DR   InterPro; IPR019471; Interferon_reg_factor-3.
DR   InterPro; IPR017855; SMAD-like_dom_sf.
DR   InterPro; IPR008984; SMAD_FHA_dom_sf.
DR   InterPro; IPR036388; WH-like_DNA-bd_sf.
DR   InterPro; IPR036390; WH_DNA-bd_sf.
DR   PANTHER; PTHR11949; INTERFERON REGULATORY FACTOR; 1.
DR   PANTHER; PTHR11949:SF7; INTERFERON REGULATORY FACTOR 8; 1.
DR   Pfam; PF00605; IRF; 1.
DR   Pfam; PF10401; IRF-3; 1.
DR   PRINTS; PR00267; INTFRNREGFCT.
DR   SMART; SM00348; IRF; 1.
DR   SMART; SM01243; IRF-3; 1.
DR   SUPFAM; SSF49879; SMAD/FHA domain; 1.
DR   SUPFAM; SSF46785; Winged helix' DNA-binding domain; 1.
DR   PROSITE; PS00601; IRF_1; 1.
DR   PROSITE; PS51507; IRF_2; 1.
DR   Genevisible; Q02556; HS.
PE   1: Evidence at protein level;
KW   Activator; Autophagy; Cytoplasm; Disease variant; DNA-binding; Nucleus;
KW   Reference proteome; Repressor; Transcription; Transcription regulation;
KW   Ubl conjugation.
FT   CHAIN           1..426
FT                   /note="Interferon regulatory factor 8"
FT                   /id="PRO_0000154564"
FT   DNA_BIND        7..114
FT                   /note="IRF tryptophan pentad repeat"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00840"
FT   VARIANT         80
FT                   /note="T -> A (in IMD32A; impairs transcriptional activity
FT                   by disrupting the interaction between IRF8 and DNA;
FT                   dbSNP:rs397514711)"
FT                   /evidence="ECO:0000269|PubMed:21524210"
FT                   /id="VAR_070084"
FT   VARIANT         81
FT                   /note="R -> K (in a breast cancer sample; somatic
FT                   mutation)"
FT                   /evidence="ECO:0000269|PubMed:16959974"
FT                   /id="VAR_036490"
FT   VARIANT         108
FT                   /note="K -> E (in IMD32B; in resting macrophages, no effect
FT                   on cytoplasmic subcellular localization; loss of nuclear
FT                   subcellular localization upon IFN-gamma induction;
FT                   decreased protein abundance; increased proteasome-dependent
FT                   degradation; increased ubiquitination and sumoylation; loss
FT                   of transcriptional repressor activity; loss of
FT                   IRF1-dependent transcriptional repressor activity; loss of
FT                   IRF1-dependent transcriptional activator activity; impairs
FT                   transcriptional activity by disrupting the interaction
FT                   between IRF8 and DNA; dbSNP:rs397514710)"
FT                   /evidence="ECO:0000269|PubMed:21524210,
FT                   ECO:0000269|PubMed:25122610"
FT                   /id="VAR_070085"
FT   VARIANT         197
FT                   /note="A -> T (in a breast cancer sample; somatic mutation;
FT                   dbSNP:rs1372132995)"
FT                   /evidence="ECO:0000269|PubMed:16959974"
FT                   /id="VAR_036491"
FT   MUTAGEN         108
FT                   /note="K->H: In resting macrophages, no effect on
FT                   cytoplasmic subcellular localization. Decreased nuclear
FT                   subcellular localization upon IFN-gamma induction. Partial
FT                   loss of IRF1-dependent transcriptional activator activity."
FT                   /evidence="ECO:0000269|PubMed:25122610"
FT   MUTAGEN         108
FT                   /note="K->Q: In resting macrophages, no effect on
FT                   cytoplasmic subcellular localization. Loss of nuclear
FT                   subcellular localization upon IFN-gamma induction. Loss of
FT                   IRF1-dependent transcriptional activator activity."
FT                   /evidence="ECO:0000269|PubMed:25122610"
FT   MUTAGEN         108
FT                   /note="K->R: In resting macrophages, no effect on
FT                   cytoplasmic subcellular localization. No effect on nuclear
FT                   subcellular localization upon IFN-gamma induction. No
FT                   effect on transcriptional activator activity. No effect on
FT                   IRF1-dependent transcriptional activator activity."
FT                   /evidence="ECO:0000269|PubMed:25122610"
SQ   SEQUENCE   426 AA;  48356 MW;  1535D1B7C83E0355 CRC64;
     MCDRNGGRRL RQWLIEQIDS SMYPGLIWEN EEKSMFRIPW KHAGKQDYNQ EVDASIFKAW
     AVFKGKFKEG DKAEPATWKT RLRCALNKSP DFEEVTDRSQ LDISEPYKVY RIVPEEEQKC
     KLGVATAGCV NEVTEMECGR SEIDELIKEP SVDDYMGMIK RSPSPPEACR SQLLPDWWAQ
     QPSTGVPLVT GYTTYDAHHS AFSQMVISFY YGGKLVGQAT TTCPEGCRLS LSQPGLPGTK
     LYGPEGLELV RFPPADAIPS ERQRQVTRKL FGHLERGVLL HSSRQGVFVK RLCQGRVFCS
     GNAVVCKGRP NKLERDEVVQ VFDTSQFFRE LQQFYNSQGR LPDGRVVLCF GEEFPDMAPL
     RSKLILVQIE QLYVRQLAEE AGKSCGAGSV MQAPEEPPPD QVFRMFPDIC ASHQRSFFRE
     NQQITV
//