ID   LTP_EBVA8               Reviewed;        3154 AA.
AC   Q1HVH9;
DT   26-MAY-2009, integrated into UniProtKB/Swiss-Prot.
DT   13-JUN-2006, sequence version 1.
DT   27-MAR-2024, entry version 62.
DE   RecName: Full=Large tegument protein deneddylase {ECO:0000255|HAMAP-Rule:MF_04044};
DE            EC=3.4.19.12 {ECO:0000255|HAMAP-Rule:MF_04044};
DE            EC=3.4.22.- {ECO:0000255|HAMAP-Rule:MF_04044};
GN   ORFNames=BPLF1;
OS   Epstein-Barr virus (strain AG876) (HHV-4) (Human herpesvirus 4).
OC   Viruses; Duplodnaviria; Heunggongvirae; Peploviricota; Herviviricetes;
OC   Herpesvirales; Orthoherpesviridae; Gammaherpesvirinae; Lymphocryptovirus;
OC   Lymphocryptovirus humangamma4; Epstein-Barr virus (strain GD1).
OX   NCBI_TaxID=82830;
OH   NCBI_TaxID=9606; Homo sapiens (Human).
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16490228; DOI=10.1016/j.virol.2006.01.015;
RA   Dolan A., Addison C., Gatherer D., Davison A.J., McGeoch D.J.;
RT   "The genome of Epstein-Barr virus type 2 strain AG876.";
RL   Virology 350:164-170(2006).
CC   -!- FUNCTION: Large tegument protein that plays multiple roles in the viral
CC       cycle. During viral entry, remains associated with the capsid while
CC       most of the tegument is detached and participates in the capsid
CC       transport toward the host nucleus. Plays a role in the routing of the
CC       capsid at the nuclear pore complex and subsequent uncoating. Within the
CC       host nucleus, acts as a deneddylase and promotes the degradation of
CC       nuclear CRLs (cullin-RING ubiquitin ligases) and thereby stabilizes
CC       nuclear CRL substrates, while cytoplasmic CRLs remain unaffected. These
CC       modifications prevent host cell cycle S-phase progression and create a
CC       favorable environment allowing efficient viral genome replication.
CC       Participates later in the secondary envelopment of capsids. Indeed,
CC       plays a linker role for the association of the outer viral tegument to
CC       the capsids together with the inner tegument protein (By similarity).
CC       Counteracts host TLR-mediated NF-kappa-B activation through both MYD88
CC       and TICAM1-dependent pathways by interfering with 'Lys-63'- and 'Lys-
CC       48'-linked ubiquitination of signaling intermediates such as TRAF6 and
CC       IKBKG. Inhibits type I interferon production by forming a tri-molecular
CC       complex with host TRIM25 and 14-3-3 thereby promoting TRIM25
CC       autoubiquitination and sequestration of the ligase into inactive
CC       protein aggregates. In turn, host RIGI is recruited to the complex but
CC       ubiquitination is severely impaired leading to inhibition of the
CC       pathway. Catalyzes also the removal of 'Lys-48'- and 'Lys-63'-linked
CC       ubiquitin chains on host TBK1 and STING1 suppressing cGAS-STING
CC       signaling in addition to the RIGI-MAVS pathway. Inhibits selective
CC       autophagy by deubiquitinating host SQSTM1. In turn, decreased SQSTM1
CC       ubiquitination fails to recruit LC3 to SQSTM1-positive aggregates. In
CC       the host nucleus, deubiquitinates topoisomerase II subunits TOP2A and
CC       TOP2B thereby stabilizing SUMOylated TOP2 which halts the DNA damage
CC       response to TOP2-induced double strand DNA breaks and promotes cell
CC       survival (By similarity). {ECO:0000250|UniProtKB:P03186,
CC       ECO:0000255|HAMAP-Rule:MF_04044}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Thiol-dependent hydrolysis of ester, thioester, amide, peptide
CC         and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-
CC         residue protein attached to proteins as an intracellular targeting
CC         signal).; EC=3.4.19.12; Evidence={ECO:0000255|HAMAP-Rule:MF_04044};
CC   -!- SUBUNIT: Interacts with host CUL1 and CUL4A; these interactions inhibit
CC       the E3 ligase activity of cullins (By similarity). Interacts with inner
CC       tegument protein. Interacts with capsid vertex specific component CVC2.
CC       Interacts with the major capsid protein/MCP (By similarity). Interacts
CC       with host TRIM25 and YWHAZ (By similarity).
CC       {ECO:0000250|UniProtKB:P03186, ECO:0000255|HAMAP-Rule:MF_04044}.
CC   -!- SUBCELLULAR LOCATION: Virion tegument {ECO:0000255|HAMAP-
CC       Rule:MF_04044}. Host cytoplasm {ECO:0000255|HAMAP-Rule:MF_04044}. Host
CC       nucleus {ECO:0000255|HAMAP-Rule:MF_04044}. Note=Tightly associated with
CC       the capsid. {ECO:0000255|HAMAP-Rule:MF_04044}.
CC   -!- SIMILARITY: Belongs to the herpesviridae large tegument protein family.
CC       {ECO:0000255|HAMAP-Rule:MF_04044}.
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DR   EMBL; DQ279927; ABB89229.1; -; Genomic_DNA.
DR   RefSeq; YP_001129449.1; NC_009334.1.
DR   SMR; Q1HVH9; -.
DR   GeneID; 5176165; -.
DR   KEGG; vg:5176165; -.
DR   Proteomes; UP000007639; 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:0019033; C:viral tegument; IEA:UniProtKB-SubCell.
DR   GO; GO:0004843; F:cysteine-type deubiquitinase activity; IEA:UniProtKB-UniRule.
DR   GO; GO:0039648; P:modulation by symbiont of host protein ubiquitination; IEA:UniProtKB-UniRule.
DR   GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR   Gene3D; 3.90.70.120; -; 1.
DR   HAMAP; MF_04044; HSV_LTP; 1.
DR   InterPro; IPR006928; Herpes_teg_USP.
DR   InterPro; IPR034702; HSV_LTP.
DR   InterPro; IPR038765; Papain-like_cys_pep_sf.
DR   PANTHER; PTHR24216:SF65; PAXILLIN-LIKE PROTEIN 1; 1.
DR   PANTHER; PTHR24216; PAXILLIN-RELATED; 1.
DR   Pfam; PF04843; Herpes_teg_N; 1.
DR   SUPFAM; SSF54001; Cysteine proteinases; 1.
DR   PROSITE; PS51521; HTUSP; 1.
PE   3: Inferred from homology;
KW   Host cytoplasm; Host nucleus; Host-virus interaction; Hydrolase;
KW   Modulation of host ubiquitin pathway by viral deubiquitinase;
KW   Modulation of host ubiquitin pathway by virus; Protease;
KW   Reference proteome; Repeat; Thiol protease; Ubl conjugation pathway;
KW   Virion; Virion tegument.
FT   CHAIN           1..3154
FT                   /note="Large tegument protein deneddylase"
FT                   /id="PRO_0000375969"
FT   DOMAIN          41..258
FT                   /note="Peptidase C76"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04044"
FT   REPEAT          335..339
FT                   /note="1"
FT   REPEAT          340..344
FT                   /note="2"
FT   REPEAT          345..349
FT                   /note="3"
FT   REPEAT          350..354
FT                   /note="4"
FT   REPEAT          355..359
FT                   /note="5"
FT   REPEAT          360..364
FT                   /note="6"
FT   REPEAT          365..369
FT                   /note="7"
FT   REPEAT          370..374
FT                   /note="8"
FT   REPEAT          375..379
FT                   /note="9"
FT   REGION          1..268
FT                   /note="Deubiquitination activity"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04044"
FT   REGION          1..30
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          319..341
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          335..379
FT                   /note="9 X 5 AA repeats of P-A-S-A-A"
FT   REGION          387..661
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          559..589
FT                   /note="Interaction with inner tegument protein"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04044"
FT   REGION          906..928
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          1148..1171
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          1413..1439
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          1649..1682
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          2588..2844
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          2859..2986
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          3000..3024
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        1..16
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        319..337
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        387..404
FT                   /note="Pro residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        419..433
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        456..494
FT                   /note="Pro residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        501..526
FT                   /note="Pro residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        527..542
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        543..614
FT                   /note="Pro residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        1656..1670
FT                   /note="Pro residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        2594..2635
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        2710..2726
FT                   /note="Pro residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        2727..2762
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        2782..2813
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        2820..2834
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        2960..2974
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        61
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04044"
FT   ACT_SITE        193
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04044"
FT   ACT_SITE        195
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04044"
FT   SITE            48
FT                   /note="Important for catalytic activity"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04044"
SQ   SEQUENCE   3154 AA;  338449 MW;  BFD719F4742849CB CRC64;
     MSNGDWGQSQ RTRGTGPVRG IRTMDVNAPG GGSGGSALRI LGTASCNQAH CKFGRFAGIQ
     CVSNCVLYLV KSFLAGRPLT SRPELDEVLD EGARLDALMR QSGILKGHEM AQLTDVPSSV
     VLRGGGRVHI YRSAEIFGLV LFPAQIANSA VVQSLAEVLH GSYNGVAQFI LYICDIYAGA
     IIIETDGSFY LFDPHCQKDA APGTPAHVRV STYAHDILQY VGAPGAQYTC VHLYFLPEAF
     ETEDPRIFML EHYGVYDFYE ANGSGFDLVG PELVSSDGEA AGTPGADSSP PVMLPFERRI
     IPYNLRPLPS RSFTSDSFPA ARYSPAKTNS PPSSPASAAP ASAAPASAAP ASAAPASAAP
     ASAAPASAAP ASAAPASAAP ASSPPLFIPI PGLGHTPGVP APSTPPRASG GAAPQTPKRK
     KGLGKDSPHK KPTSGRRLPL SSTTDTEDDQ LPRTHVPPHR PPSAARLPPP VIPIPHQSPP
     ASPTPRPAPV STIAPSVTPS PRLPLQIPIP LPQAAPSNPE IPLTTPSPSP TAAAAPTATT
     LSPPPTQQQP PQSAAPAPSP PPTQQQPPQS AAPAPSPLLP QQQPPPSAAR APSPLPPQQQ
     PLPSATPAPP HAQQLPPSAT TLEPEKNNPS AADRAGTEIS PSPPFGQQPS FGDDASGGSG
     LVRYLSDLEE PFLSMSDSEE AESDLASDIP TTEDEDMFED EVFSNSLESG SSAPTSPITL
     DTARSQYYQT TFDIETPEMD FVPLESNIAR IAGHTYQEQA IVYDPASNRE VPEADALSMI
     DYLLVTVVLE QGLIRSRDRS AVLNLLEFLK DWSGHLQVPT LDLEQLLTSE LNIQNLANML
     SENKGRAGEF HEHLAAKLEA CLPSLATKDA VRVDAGAKML AEIPQLAESG DGKFDLEAAR
     RRLTDLLSGG DQEGEEGGGE PEDHSIYRGP HVDVPLVLDD ESWKRLLSLA EAARTAVARQ
     QAGVDEEDVR FLALLTAIEY GAPPAASVPP FVHNVPVRSK NAALHVRRCT ADIRDKVASA
     ASDYLSYLED PSLPTVMDFD DLLTHLRHTC QIIASLPLLN IRYTSIEWDY RELLYLGTAL
     SDMSGIPWPL ERVEEDDPSI APLPEFETVA KKQKELETTR ENEKRLRTIL DDIEAMLGLA
     GVASAPGAPI SPASPSATPA NHDNPEATPP LADTAALTIP VIEKYIANAG SIVGAAKNPT
     YIRLRDTIQQ IVRSKKYLMN ILKSITFYTI DNYIASFEES IDHLYRDLPV LDPEVQDGID
     RILDPMVSEA LHTFEMGNRL TLEPARLVAL QNFATHSTLK ETAAAVNLLP GLLAVYDATV
     TGQAPEDALR LLSGLQNQLS QTLIPGKLKK RFLSYLQKLK NNNNDQLRQK EVQAWRLEAE
     GFKPATEEQL EAFLDTAPNK ELKRQYEKKL RQLMETGRKE KEKLREQEDK ERRERRAREA
     NEAWARIRKA LGARPEPAPT SPDDWNTLLA SLLPDNTDSA AAAAAAVARN TDILDSLTQI
     LAAMLLGITR VRRERLRSLL VDDGGAAERM EAVEPGWFTE IETGPLARLD AWPATPAATA
     KEGGGGRGAE EAAGALFRAR TAADAIRSAL AQTRQALQSP DMKSAVVNTD LEAPYAEYER
     GLAGLLEKRR SAEAALTAIV SEYVDRTLPE ATNDPGQANL PPPPTIPQAT APPRLASDSA
     LWPKKPQLLT RRERDDLLQA TGDFFSELLT EAEAAEVRAL EEQVRESQTL MAKAHEMAAS
     TRRGFHTALE AVLSRSRDEA PDDELRSLLP SPPKAPVQAP LEAALARAAA GNGSWPYRKS
     LAAAKWIRGI CEAVRGLSEG ALALAGGVGA WLNLAAAADG EIHELTRLLE VEGMAQNSMD
     GMEELRLALA TLDPKRVAGG KETVADWKRR LSRLEAIIQE AQEESQLQGT LQDLVTQARG
     HTDPRQLKIV VEAARGLALG ASAGSQYALL KDKLLRYASA KQSFLAFYET AQPTVFVKHP
     LTNNLPLLIT ISAPPTGWGN GAPTRRAQFL AAAGPAKYAG TLWLETESPC DPLNPAYVSA
     DTQEPLNYIP VYHNFLEYVM PTVLENPEAF SLTPAGRPQA IGPPQDDQER RRRTLASVAS
     ARLSAAAADS YWDTWPDVES NAGELLREYV SAPKALMEDL ADNPIVAMTL LAHASLIASR
     NHPPYPAPAT DREVILLEQR EMMALLVGTH PAYAAAFLGA PSFYAGLGLV SALARDGGLG
     DLLSDSVLTY RLVRSPASGR GGMPSTTRGS NDGEDARRLT RHRIAGPPTG FIFFQDAWEE
     MDTRAALWPH PEFLGLVHNQ STARARACML LLARRCFAPE ALQQLWHSLR PLEGPVAFQD
     YLRDFVKQAY TRGEELPRAE GLEVPRETPS SYGTVTGRAL RNLMPYGTPI TGPKRGSGDT
     IPVSVFEAAV AAAFLGRPLT LFVSSQYLFN LKTLGQVRVV APLLYCDGHS EPFRSLVETI
     SLNFLQDLDG YSESFEPEMS IFARQAVWLR ELLTEARAAK PKEARPPTVA ILANRKNIIW
     KCFTYRHNLP DVQFYFNAAG ASRWPTDVLN PSFYEHEDPP LPVGYQLPPN PRNVQELFSG
     FPPRVGHGLV SGDGFQSADN TPASSDRLQQ LGGGETDQGE EGSTTAESEA SGPPSPQSPL
     LEKVAPGRPR DWLSPTSSPR DVTVTPGLAA PITLPGPRLM ARPYFGAETR ASESPDRSPG
     TSPRPWPKDS LELLPQPAPQ QPPSSPWASE QGPIVYTLSP NSTPSTASGS QKKHTIQIPG
     LVPSQKPSYP PSAPYKPGQS TGGIAPTPSA ASLTTFGLQP QDTQASSQDP PYGHSIMQRE
     KKQQGGREEA AEIRPSATRL PTAVGLRPRA PVVAAGAAAS ATPAFDPGEA PSGFPIPQAP
     ALGSGLAAPA HTPVGALAPR PQKTQAQRPQ DAAALPTPTI KAVGARPVPK ATGALAAGAR
     PRGQPTAAPP SAASPPRVSL PVRSRQQQSP AIPLPPMHSG SEPGARPEVR LSQYRHAGPQ
     TYTVRKEAPP SAASQLPKMP KCKDSMYYPP SGSARYPAPF QALSFSQSVA SPAPSSDQTT
     LLWNTPSVVT QFLSIEDIIR EVVTGGSTSG DLVVPSGSPS SLSTAAPEQD LRYSLTLSQA
     SRVLSRFVSQ LRRKLERSTH RLIADLERLK FLYL
//