ORF52_HHV8P
ID ORF52_HHV8P Reviewed; 131 AA.
AC Q2HR80; D0UZR5;
DT 16-OCT-2013, integrated into UniProtKB/Swiss-Prot.
DT 15-MAY-2007, sequence version 1.
DT 23-FEB-2022, entry version 56.
DE RecName: Full=Tegument protein ORF52 {ECO:0000305};
DE AltName: Full=Kaposi's sarcoma-associated herpesvirus inhibitor of cGAS {ECO:0000303|PubMed:27009954};
DE Short=KicGAS {ECO:0000303|PubMed:27009954};
GN Name=ORF52 {ECO:0000303|PubMed:26320998};
OS Human herpesvirus 8 type P (isolate GK18) (HHV-8) (Kaposi's
OS sarcoma-associated herpesvirus).
OC Viruses; Duplodnaviria; Heunggongvirae; Peploviricota; Herviviricetes;
OC Herpesvirales; Herpesviridae; Gammaherpesvirinae; Rhadinovirus.
OX NCBI_TaxID=868565;
OH NCBI_TaxID=9606; Homo sapiens (Human).
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10400794; DOI=10.1128/jvi.73.8.6953-6963.1999;
RA Glenn M., Rainbow L., Aurade F., Davison A., Schulz T.F.;
RT "Identification of a spliced gene from Kaposi's sarcoma-associated
RT herpesvirus encoding a protein with similarities to latent membrane
RT proteins 1 and 2A of Epstein-Barr virus.";
RL J. Virol. 73:6953-6963(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16760382; DOI=10.1099/vir.0.81919-0;
RA Rezaee S.A.R., Cunningham C., Davison A.J., Blackbourn D.J.;
RT "Kaposi's sarcoma-associated herpesvirus immune modulation: an overview.";
RL J. Gen. Virol. 87:1781-1804(2006).
RN [3]
RP FUNCTION, INTERACTION WITH HOST CGAS, AND SUBCELLULAR LOCATION.
RX PubMed=26320998; DOI=10.1016/j.chom.2015.07.015;
RA Wu J.J., Li W., Shao Y., Avey D., Fu B., Gillen J., Hand T., Ma S., Liu X.,
RA Miley W., Konrad A., Neipel F., Stuerzl M., Whitby D., Li H., Zhu F.;
RT "Inhibition of cGAS DNA Sensing by a Herpesvirus Virion Protein.";
RL Cell Host Microbe 18:333-344(2015).
RN [4]
RP SUBCELLULAR LOCATION, AND PHOSPHORYLATION AT SER-123.
RX PubMed=27009954; DOI=10.1128/jvi.02675-15;
RA Li W., Avey D., Fu B., Wu J.J., Ma S., Liu X., Zhu F.;
RT "Kaposi's sarcoma-associated herpesvirus inhibitor of cGAS (KicGAS),
RT encoded by ORF52, is an abundant tegument protein and is required for
RT production of infectious progeny viruses.";
RL J. Virol. 90:5329-5342(2016).
RN [5]
RP FUNCTION, AND INTERACTION WITH CGAS AND PQBP1.
RX PubMed=28712728; DOI=10.1016/j.molcel.2017.06.020;
RA Morchikh M., Cribier A., Raffel R., Amraoui S., Cau J., Severac D.,
RA Dubois E., Schwartz O., Bennasser Y., Benkirane M.;
RT "HEXIM1 and NEAT1 Long non-coding RNA form a multi-subunit complex that
RT regulates DNA-mediated innate immune response.";
RL Mol. Cell 67:387-399(2017).
RN [6]
RP FUNCTION, DNA-BINDING, INTERACTION WITH HOST CGAS, AND MUTAGENESIS OF
RP 5-ARG--LYS-20; 29-ARG--LYS-33; 42-ARG--LYS-51; 68-LYS--ARG-73;
RP 75-ARG--LYS-92; 106-GLY--ASP-131 AND 117-ARG--ARG-120.
RX PubMed=34015248; DOI=10.1016/j.molcel.2021.05.002;
RA Xu G., Liu C., Zhou S., Li Q., Feng Y., Sun P., Feng H., Gao Y., Zhu J.,
RA Luo X., Zhan Q., Liu S., Zhu S., Deng H., Li D., Gao P.;
RT "Viral tegument proteins restrict cGAS-DNA phase separation to mediate
RT immune evasion.";
RL Mol. Cell 81:2823-2837(2021).
RN [7]
RP FUNCTION, DNA-BINDING, SUBUNIT, INTERACTION WITH HOST CGAS, AND MUTAGENESIS
RP OF LEU-17; ILE-21; LEU-24; GLU-27; ASN-28; LEU-31; ILE-70; VAL-74; VAL-87;
RP LEU-91; LEU-96; ARG-97; ILE-98; VAL-100 AND 117-ARG--ARG-120.
RX PubMed=34387695; DOI=10.1093/nar/gkab689;
RA Bhowmik D., Du M., Tian Y., Ma S., Wu J., Chen Z., Yin Q., Zhu F.;
RT "Cooperative DNA binding mediated by KicGAS/ORF52 oligomerization allows
RT inhibition of DNA-induced phase separation and activation of cGAS.";
RL Nucleic Acids Res. 49:9389-9403(2021).
CC -!- FUNCTION: Plays a role in the inhibition of host innate immune system
CC by targeting the CGAS enzymatic activity which is the principal
CC cytosolic DNA sensor that detects invading viral DNA (PubMed:26320998,
CC PubMed:34015248, PubMed:34387695). Acts by inhibiting CGAS-DNA phase
CC separation: directly binds double-stranded DNA (dsDNA) in a length
CC dependent but sequence independent manner and is able to form DNA-
CC induced phase separation in infected cells (PubMed:34015248,
CC PubMed:34387695). DNA phase separation of ORF52 mediates disruption of
CC liquid-like droplets in which CGAS is activated, thereby preventing
CC CGAS activity (PubMed:34015248, PubMed:34387695). Targets also the HDP-
CC RNP complex composed of DNA-PK subunits and paraspeckle proteins
CC (PubMed:28712728). This complex is a key nuclear regulator of DNA-
CC mediated activation of innate immune response through the cGAS-STING
CC pathway (PubMed:28712728). {ECO:0000269|PubMed:26320998,
CC ECO:0000269|PubMed:28712728, ECO:0000269|PubMed:34015248,
CC ECO:0000269|PubMed:34387695}.
CC -!- SUBUNIT: Homooligomer; homooligomerizes and binds double-stranded DNA
CC (dsDNA) cooperatively (PubMed:34387695). Interacts with host CGAS
CC (PubMed:26320998, PubMed:28712728, PubMed:34015248, PubMed:34387695).
CC Interacts with PQBP1 (PubMed:28712728). {ECO:0000269|PubMed:26320998,
CC ECO:0000269|PubMed:28712728, ECO:0000269|PubMed:34015248,
CC ECO:0000269|PubMed:34387695}.
CC -!- INTERACTION:
CC Q2HR80; Q77UV9: KIE-2; Xeno; NbExp=3; IntAct=EBI-2608700, EBI-2608731;
CC Q2HR80; C7E599: ORF26; Xeno; NbExp=2; IntAct=EBI-2608700, EBI-2608736;
CC Q2HR80; O40931: ORF39; Xeno; NbExp=3; IntAct=EBI-2608700, EBI-2608673;
CC Q2HR80; Q76RG4: ORF53; Xeno; NbExp=2; IntAct=EBI-2608700, EBI-2608592;
CC Q2HR80; D0UZU4: ORF75; Xeno; NbExp=3; IntAct=EBI-2608700, EBI-2608638;
CC -!- SUBCELLULAR LOCATION: Host cytoplasm {ECO:0000269|PubMed:26320998,
CC ECO:0000269|PubMed:27009954}. Virion tegument
CC {ECO:0000269|PubMed:27009954}.
CC -!- SIMILARITY: Belongs to the herpesviridae BLRF2 family. {ECO:0000305}.
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DR EMBL; AF148805; ABD28903.1; -; Genomic_DNA.
DR RefSeq; YP_001129405.1; NC_009333.1.
DR SMR; Q2HR80; -.
DR BioGRID; 1776999; 4.
DR IntAct; Q2HR80; 8.
DR PRIDE; Q2HR80; -.
DR DNASU; 4961496; -.
DR GeneID; 4961496; -.
DR KEGG; vg:4961496; -.
DR Proteomes; UP000000942; Genome.
DR GO; GO:0030430; C:host cell cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0019033; C:viral tegument; IEA:UniProtKB-SubCell.
DR GO; GO:0003690; F:double-stranded DNA binding; IDA:UniProtKB.
DR GO; GO:0039503; P:suppression by virus of host innate immune response; IDA:UniProtKB.
DR InterPro; IPR008642; Herpes_BLRF2.
DR Pfam; PF05812; Herpes_BLRF2; 1.
PE 1: Evidence at protein level;
KW DNA-binding; Host cytoplasm; Host-virus interaction;
KW Inhibition of host innate immune response by virus; Phosphoprotein;
KW Reference proteome; Viral immunoevasion; Virion; Virion tegument.
FT CHAIN 1..131
FT /note="Tegument protein ORF52"
FT /id="PRO_0000423777"
FT REGION 103..131
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 123
FT /note="Phosphoserine; by host"
FT /evidence="ECO:0000269|PubMed:27009954"
FT MUTAGEN 5..20
FT /note="RGRPKKDLTMEDLTAK->AGAPAADLTMEDLTAA: In M1; decreased
FT formation of DNA-induced phase separation, leading to
FT decreased ability to inhibit host CGAS."
FT /evidence="ECO:0000269|PubMed:34015248"
FT MUTAGEN 17
FT /note="L->A: Does not affect homooligomerization; does not
FT affect ability to inhibit host CGAS."
FT /evidence="ECO:0000269|PubMed:34387695"
FT MUTAGEN 21
FT /note="I->A: Decreased homooligomerization, formation of
FT DNA-induced phase separation and ability to inhibit host
FT CGAS."
FT /evidence="ECO:0000269|PubMed:34387695"
FT MUTAGEN 24
FT /note="L->A: Decreased homooligomerization, formation of
FT DNA-induced phase separation and ability to inhibit host
FT CGAS."
FT /evidence="ECO:0000269|PubMed:34387695"
FT MUTAGEN 27
FT /note="E->A: Does not affect homooligomerization; does not
FT affect ability to inhibit host CGAS."
FT /evidence="ECO:0000269|PubMed:34387695"
FT MUTAGEN 28
FT /note="N->A: Decreased homooligomerization, formation of
FT DNA-induced phase separation and ability to inhibit host
FT CGAS."
FT /evidence="ECO:0000269|PubMed:34387695"
FT MUTAGEN 29..33
FT /note="RELRK->AELAA: In M2; decreased formation of DNA-
FT induced phase separation, leading to decreased ability to
FT inhibit host CGAS."
FT /evidence="ECO:0000269|PubMed:34015248"
FT MUTAGEN 31
FT /note="L->A: Decreased homooligomerization, formation of
FT DNA-induced phase separation and ability to inhibit host
FT CGAS."
FT /evidence="ECO:0000269|PubMed:34387695"
FT MUTAGEN 42..51
FT /note="RDRPLTATEK->ADAPLTATEA: In M3; decreased formation
FT of DNA-induced phase separation, leading to decreased
FT ability to inhibit host CGAS."
FT /evidence="ECO:0000269|PubMed:34015248"
FT MUTAGEN 68..73
FT /note="KKIEAR->AAEIAA: In M4; does not affect formation of
FT DNA-induced phase separation."
FT /evidence="ECO:0000269|PubMed:34015248"
FT MUTAGEN 70
FT /note="I->A: Does not affect DNA-binding; does not affect
FT ability to inhibit host CGAS."
FT /evidence="ECO:0000269|PubMed:34387695"
FT MUTAGEN 74
FT /note="V->A: Does not affect DNA-binding; does not affect
FT ability to inhibit host CGAS."
FT /evidence="ECO:0000269|PubMed:34387695"
FT MUTAGEN 75..92
FT /note="RTIFSKVVTQKQVDDALK->ATIFSAVVTQAQVDDALA: In M5;
FT decreased formation of DNA-induced phase separation,
FT leading to decreased ability to inhibit host CGAS."
FT /evidence="ECO:0000269|PubMed:34015248"
FT MUTAGEN 87
FT /note="V->A: Does not affect DNA-binding; does not affect
FT ability to inhibit host CGAS."
FT /evidence="ECO:0000269|PubMed:34387695"
FT MUTAGEN 91
FT /note="L->A: Does not affect DNA-binding; does not affect
FT ability to inhibit host CGAS."
FT /evidence="ECO:0000269|PubMed:34387695"
FT MUTAGEN 96
FT /note="L->A: Does not affect DNA-binding; does not affect
FT ability to inhibit host CGAS."
FT /evidence="ECO:0000269|PubMed:34387695"
FT MUTAGEN 97
FT /note="R->A: Decreased DNA-binding and ability to inhibit
FT host CGAS."
FT /evidence="ECO:0000269|PubMed:34387695"
FT MUTAGEN 98
FT /note="I->A: Does not affect DNA-binding; does not affect
FT ability to inhibit host CGAS."
FT /evidence="ECO:0000269|PubMed:34387695"
FT MUTAGEN 100
FT /note="V->A: Does not affect DNA-binding; does not affect
FT ability to inhibit host CGAS."
FT /evidence="ECO:0000269|PubMed:34387695"
FT MUTAGEN 106..131
FT /note="Missing: In M7; abolished formation of DNA-induced
FT phase separation, preventing ability to inhibit host CGAS."
FT /evidence="ECO:0000269|PubMed:34015248"
FT MUTAGEN 117..120
FT /note="RRRR->AAAA: In M8; abolished formation of DNA-
FT induced phase separation, preventing ability to inhibit
FT host CGAS."
FT /evidence="ECO:0000269|PubMed:34015248,
FT ECO:0000269|PubMed:34387695"
FT MUTAGEN 117..120
FT /note="RRRR->KKKK: Does not affect formation of DNA-induced
FT phase separation."
FT /evidence="ECO:0000269|PubMed:34387695"
SQ SEQUENCE 131 AA; 13997 MW; CE3399C0C1D143D9 CRC64;
MAAPRGRPKK DLTMEDLTAK ISQLTVENRE LRKALGSTAD PRDRPLTATE KEAQLTATVG
ALSAAAAKKI EARVRTIFSK VVTQKQVDDA LKGLSLRIDV CMSDGGTAKP PPGANNRRRR
GASTTRAGVD D
