ID TRI65_HUMAN Reviewed; 517 AA.
AC Q6PJ69; Q4G0F0; Q6DKJ6; Q9BRP6;
DT 05-SEP-2006, integrated into UniProtKB/Swiss-Prot.
DT 18-MAY-2010, sequence version 3.
DT 24-JAN-2024, entry version 163.
DE RecName: Full=E3 ubiquitin-protein ligase TRIM65;
DE EC=2.3.2.27 {ECO:0000269|PubMed:24778252, ECO:0000269|PubMed:31310649};
DE AltName: Full=Tripartite motif-containing protein 65;
GN Name=TRIM65;
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 [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S.,
RA Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E.,
RA Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K.,
RA LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J.,
RA Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A.,
RA Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K.,
RA Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in the
RT human lineage.";
RL Nature 440:1045-1049(2006).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS GLY-222 AND PRO-509.
RC TISSUE=Brain, Liver, and Lymph;
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 [3]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [4]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=22223895; DOI=10.1074/mcp.m111.015131;
RA Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T.,
RA Giglione C.;
RT "Comparative large-scale characterisation of plant vs. mammal proteins
RT reveals similar and idiosyncratic N-alpha acetylation features.";
RL Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012).
RN [5]
RP FUNCTION, SUBCELLULAR LOCATION, CATALYTIC ACTIVITY, AND SUBUNIT.
RX PubMed=24778252; DOI=10.1073/pnas.1322545111;
RA Li S., Wang L., Fu B., Berman M.A., Diallo A., Dorf M.E.;
RT "TRIM65 regulates microRNA activity by ubiquitination of TNRC6.";
RL Proc. Natl. Acad. Sci. U.S.A. 111:6970-6975(2014).
RN [6]
RP UBIQUITINATION AT LYS-206 BY SALMONELLA TYPHIMURIUM SOPA (MICROBIAL
RP INFECTION).
RX PubMed=28084320; DOI=10.1038/ncomms14004;
RA Fiskin E., Bhogaraju S., Herhaus L., Kalayil S., Hahn M., Dikic I.;
RT "Structural basis for the recognition and degradation of host TRIM proteins
RT by Salmonella effector SopA.";
RL Nat. Commun. 8:14004-14004(2017).
RN [7]
RP FUNCTION, AND INTERACTION WITH ARRDC4.
RX PubMed=28594402; DOI=10.1038/cddis.2017.257;
RA Meng J., Yao Z., He Y., Zhang R., Zhang Y., Yao X., Yang H., Chen L.,
RA Zhang Z., Zhang H., Bao X., Hu G., Wu T., Cheng J.;
RT "ARRDC4 regulates enterovirus 71-induced innate immune response by
RT promoting K63 polyubiquitination of MDA5 through TRIM65.";
RL Cell Death Dis. 8:e2866-e2866(2017).
RN [8]
RP FUNCTION.
RX PubMed=31160576; DOI=10.1038/s41419-019-1660-8;
RA Pan X., Chen Y., Shen Y., Tantai J.;
RT "Knockdown of TRIM65 inhibits autophagy and cisplatin resistance in
RT A549/DDP cells by regulating miR-138-5p/ATG7.";
RL Cell Death Dis. 10:429-429(2019).
RN [9]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=31310649; DOI=10.1093/jmcb/mjz077;
RA Li Y., Huang X., Guo F., Lei T., Li S., Monaghan-Nichols P., Jiang Z.,
RA Xin H.B., Fu M.;
RT "TRIM65 E3 ligase targets VCAM-1 degradation to limit LPS-induced lung
RT inflammation.";
RL J. Mol. Cell Biol. 12:190-201(2020).
RN [10]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=34512673; DOI=10.3389/fimmu.2021.741839;
RA Tang T., Li P., Zhou X., Wang R., Fan X., Yang M., Qi K.;
RT "The E3 Ubiquitin Ligase TRIM65 Negatively Regulates Inflammasome
RT Activation Through Promoting Ubiquitination of NLRP3.";
RL Front. Immunol. 12:741839-741839(2021).
RN [11] {ECO:0007744|PDB:7JL0, ECO:0007744|PDB:7JL2, ECO:0007744|PDB:7JL4}
RP X-RAY CRYSTALLOGRAPHY (1.92 ANGSTROMS) OF 312-502, AND FUNCTION.
RX PubMed=33373584; DOI=10.1016/j.molcel.2020.11.047;
RA Kato K., Ahmad S., Zhu Z., Young J.M., Mu X., Park S., Malik H.S., Hur S.;
RT "Structural analysis of RIG-I-like receptors reveals ancient rules of
RT engagement between diverse RNA helicases and TRIM ubiquitin ligases.";
RL Mol. Cell 81:599-613.e8(2021).
CC -!- FUNCTION: E3 ubiquitin ligase that plays a role in several processes
CC including innate immnity, autophagy or inflammation (PubMed:28594402,
CC PubMed:34512673). Negatively regulates miRNAs by modulating the
CC ubiquitination and stability of TNRC6A, a protein involved in RNA-
CC mediated gene silencing by both micro-RNAs (miRNAs) and short
CC interfering RNAs (PubMed:24778252). This ubiquitination results in the
CC suppressed expression of miR-138-5p leading to increased autophagy
CC (PubMed:31160576). Upon enteroviral infection, promotes 'Lys-63'-
CC mediated ubiquitination activation of IFIH1/MDA5 leading to innate
CC signaling cascade (PubMed:28594402). Mechanistically, selectively
CC recognizes MDA5 filaments that occur on dsRNAs (PubMed:33373584). Plays
CC also a role in limitation of inflammation through different mechanisms.
CC First, promotes 'Lys-48'-mediated ubiquitination of VCAM1 leading to
CC its degradation and limitation of LPS-induced lung inflammation
CC (PubMed:31310649). In addition, negatively regulates inflammasome
CC activation by promoting 'lys48'-linked ubiquitination of NLRP3 which is
CC critical for the inhibition of NLRP3 inflammasome activation in resting
CC macrophages (PubMed:34512673). {ECO:0000269|PubMed:24778252,
CC ECO:0000269|PubMed:28594402, ECO:0000269|PubMed:31160576,
CC ECO:0000269|PubMed:31310649, ECO:0000269|PubMed:33373584,
CC ECO:0000269|PubMed:34512673}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine +
CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-
CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.;
CC EC=2.3.2.27; Evidence={ECO:0000269|PubMed:24778252,
CC ECO:0000269|PubMed:31310649};
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Homo-multimerizes (PubMed:24778252). Interacts with ARRDC4
CC (PubMed:28594402). {ECO:0000269|PubMed:24778252,
CC ECO:0000269|PubMed:28594402}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:24778252,
CC ECO:0000269|PubMed:34512673}.
CC -!- SIMILARITY: Belongs to the TRIM/RBCC family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH73831.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AC087289; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC006138; AAH06138.1; -; mRNA.
DR EMBL; BC021259; AAH21259.2; -; mRNA.
DR EMBL; BC073831; AAH73831.1; ALT_INIT; mRNA.
DR EMBL; BC098412; AAH98412.1; -; mRNA.
DR CCDS; CCDS11732.1; -.
DR RefSeq; NP_001243053.1; NM_001256124.1.
DR RefSeq; NP_775818.2; NM_173547.3.
DR PDB; 7JL0; EM; 4.30 A; B=312-502.
DR PDB; 7JL2; EM; 4.30 A; B/D/F=312-502.
DR PDB; 7JL4; X-ray; 1.92 A; A/B/C=312-502.
DR PDBsum; 7JL0; -.
DR PDBsum; 7JL2; -.
DR PDBsum; 7JL4; -.
DR AlphaFoldDB; Q6PJ69; -.
DR EMDB; EMD-22368; -.
DR EMDB; EMD-22370; -.
DR SMR; Q6PJ69; -.
DR BioGRID; 128382; 79.
DR IntAct; Q6PJ69; 18.
DR MINT; Q6PJ69; -.
DR STRING; 9606.ENSP00000269383; -.
DR GlyGen; Q6PJ69; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q6PJ69; -.
DR PhosphoSitePlus; Q6PJ69; -.
DR BioMuta; TRIM65; -.
DR DMDM; 296453004; -.
DR EPD; Q6PJ69; -.
DR jPOST; Q6PJ69; -.
DR MassIVE; Q6PJ69; -.
DR MaxQB; Q6PJ69; -.
DR PaxDb; 9606-ENSP00000269383; -.
DR PeptideAtlas; Q6PJ69; -.
DR ProteomicsDB; 67192; -.
DR Pumba; Q6PJ69; -.
DR Antibodypedia; 19643; 117 antibodies from 16 providers.
DR DNASU; 201292; -.
DR Ensembl; ENST00000269383.8; ENSP00000269383.3; ENSG00000141569.12.
DR GeneID; 201292; -.
DR KEGG; hsa:201292; -.
DR MANE-Select; ENST00000269383.8; ENSP00000269383.3; NM_173547.4; NP_775818.2.
DR UCSC; uc002jpx.4; human.
DR AGR; HGNC:27316; -.
DR CTD; 201292; -.
DR DisGeNET; 201292; -.
DR GeneCards; TRIM65; -.
DR HGNC; HGNC:27316; TRIM65.
DR HPA; ENSG00000141569; Low tissue specificity.
DR MIM; 619408; gene.
DR neXtProt; NX_Q6PJ69; -.
DR OpenTargets; ENSG00000141569; -.
DR PharmGKB; PA134877726; -.
DR VEuPathDB; HostDB:ENSG00000141569; -.
DR eggNOG; KOG2177; Eukaryota.
DR GeneTree; ENSGT00940000161851; -.
DR HOGENOM; CLU_013137_0_2_1; -.
DR InParanoid; Q6PJ69; -.
DR OMA; FKHGQHY; -.
DR OrthoDB; 828004at2759; -.
DR PhylomeDB; Q6PJ69; -.
DR TreeFam; TF351090; -.
DR PathwayCommons; Q6PJ69; -.
DR SignaLink; Q6PJ69; -.
DR SIGNOR; Q6PJ69; -.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 201292; 15 hits in 1191 CRISPR screens.
DR ChiTaRS; TRIM65; human.
DR GenomeRNAi; 201292; -.
DR Pharos; Q6PJ69; Tbio.
DR PRO; PR:Q6PJ69; -.
DR Proteomes; UP000005640; Chromosome 17.
DR RNAct; Q6PJ69; Protein.
DR Bgee; ENSG00000141569; Expressed in buccal mucosa cell and 108 other cell types or tissues.
DR ExpressionAtlas; Q6PJ69; baseline and differential.
DR Genevisible; Q6PJ69; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProt.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:UniProt.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0140374; P:antiviral innate immune response; IEA:Ensembl.
DR GO; GO:0050728; P:negative regulation of inflammatory response; IDA:UniProt.
DR GO; GO:0010508; P:positive regulation of autophagy; IMP:UniProtKB.
DR GO; GO:0032727; P:positive regulation of interferon-alpha production; IEA:Ensembl.
DR GO; GO:0032728; P:positive regulation of interferon-beta production; IDA:UniProt.
DR GO; GO:0032461; P:positive regulation of protein oligomerization; IEA:Ensembl.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IEA:Ensembl.
DR GO; GO:0070936; P:protein K48-linked ubiquitination; IDA:UniProt.
DR GO; GO:0070534; P:protein K63-linked ubiquitination; IDA:UniProt.
DR GO; GO:0060337; P:type I interferon-mediated signaling pathway; IEA:Ensembl.
DR CDD; cd19835; Bbox2_TRIM65_C-IV; 1.
DR CDD; cd16609; RING-HC_TRIM65_C-IV; 1.
DR CDD; cd12896; SPRY_PRY_TRIM65; 1.
DR Gene3D; 2.60.120.920; -; 1.
DR Gene3D; 3.30.160.60; Classic Zinc Finger; 1.
DR Gene3D; 3.30.40.10; Zinc/RING finger domain, C3HC4 (zinc finger); 1.
DR InterPro; IPR001870; B30.2/SPRY.
DR InterPro; IPR043136; B30.2/SPRY_sf.
DR InterPro; IPR003879; Butyrophylin_SPRY.
DR InterPro; IPR013320; ConA-like_dom_sf.
DR InterPro; IPR003877; SPRY_dom.
DR InterPro; IPR048222; TRIM65_SPRY_PRY.
DR InterPro; IPR000315; Znf_B-box.
DR InterPro; IPR018957; Znf_C3HC4_RING-type.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR InterPro; IPR017907; Znf_RING_CS.
DR PANTHER; PTHR25465; B-BOX DOMAIN CONTAINING; 1.
DR PANTHER; PTHR25465:SF29; TRIPARTITE MOTIF-CONTAINING PROTEIN 65; 1.
DR Pfam; PF00622; SPRY; 1.
DR Pfam; PF00643; zf-B_box; 1.
DR Pfam; PF00097; zf-C3HC4; 1.
DR PRINTS; PR01407; BUTYPHLNCDUF.
DR SMART; SM00336; BBOX; 1.
DR SMART; SM00184; RING; 1.
DR SMART; SM00449; SPRY; 1.
DR SUPFAM; SSF57845; B-box zinc-binding domain; 1.
DR SUPFAM; SSF49899; Concanavalin A-like lectins/glucanases; 1.
DR SUPFAM; SSF57850; RING/U-box; 1.
DR PROSITE; PS50188; B302_SPRY; 1.
DR PROSITE; PS50119; ZF_BBOX; 1.
DR PROSITE; PS00518; ZF_RING_1; 1.
DR PROSITE; PS50089; ZF_RING_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Coiled coil; Cytoplasm; Immunity;
KW Innate immunity; Isopeptide bond; Metal-binding; Phosphoprotein;
KW Reference proteome; Transferase; Ubl conjugation; Zinc; Zinc-finger.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0007744|PubMed:19413330,
FT ECO:0007744|PubMed:22223895"
FT CHAIN 2..517
FT /note="E3 ubiquitin-protein ligase TRIM65"
FT /id="PRO_0000249191"
FT DOMAIN 313..506
FT /note="B30.2/SPRY"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00548"
FT ZN_FING 12..51
FT /note="RING-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175"
FT ZN_FING 90..137
FT /note="B box-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00024"
FT REGION 75..94
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 139..227
FT /evidence="ECO:0000255"
FT COMPBIAS 80..94
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 95
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00024"
FT BINDING 98
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00024"
FT BINDING 117
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00024"
FT BINDING 125
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00024"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0007744|PubMed:19413330,
FT ECO:0007744|PubMed:22223895"
FT MOD_RES 185
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8BFW4"
FT CROSSLNK 206
FT /note="(Microbial infection) Glycyl lysine isopeptide (Lys-
FT Gly) (interchain with G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:28084320"
FT VARIANT 222
FT /note="V -> G (in dbSNP:rs7222757)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_060245"
FT VARIANT 364
FT /note="G -> R (in dbSNP:rs34593741)"
FT /id="VAR_057224"
FT VARIANT 366
FT /note="G -> S (in dbSNP:rs9892938)"
FT /id="VAR_057225"
FT VARIANT 509
FT /note="L -> P (in dbSNP:rs3760128)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_060246"
FT HELIX 321..326
FT /evidence="ECO:0007829|PDB:7JL4"
FT HELIX 327..329
FT /evidence="ECO:0007829|PDB:7JL4"
FT TURN 337..339
FT /evidence="ECO:0007829|PDB:7JL4"
FT STRAND 344..347
FT /evidence="ECO:0007829|PDB:7JL4"
FT TURN 348..351
FT /evidence="ECO:0007829|PDB:7JL4"
FT STRAND 352..355
FT /evidence="ECO:0007829|PDB:7JL4"
FT STRAND 369..376
FT /evidence="ECO:0007829|PDB:7JL4"
FT STRAND 381..400
FT /evidence="ECO:0007829|PDB:7JL4"
FT STRAND 422..427
FT /evidence="ECO:0007829|PDB:7JL4"
FT STRAND 429..436
FT /evidence="ECO:0007829|PDB:7JL4"
FT STRAND 439..444
FT /evidence="ECO:0007829|PDB:7JL4"
FT STRAND 450..456
FT /evidence="ECO:0007829|PDB:7JL4"
FT TURN 457..460
FT /evidence="ECO:0007829|PDB:7JL4"
FT STRAND 461..466
FT /evidence="ECO:0007829|PDB:7JL4"
FT STRAND 468..470
FT /evidence="ECO:0007829|PDB:7JL4"
FT STRAND 472..478
FT /evidence="ECO:0007829|PDB:7JL4"
FT STRAND 485..491
FT /evidence="ECO:0007829|PDB:7JL4"
FT STRAND 496..499
FT /evidence="ECO:0007829|PDB:7JL4"
SQ SEQUENCE 517 AA; 57353 MW; 1382A178CB99BBBA CRC64;
MAAQLLEEKL TCAICLGLYQ DPVTLPCGHN FCGACIRDWW DRCGKACPEC REPFPDGAEL
RRNVALSGVL EVVRAGPARD PGPDPGPGPD PAARCPRHGR PLELFCRTEG RCVCSVCTVR
ECRLHERALL DAERLKREAQ LRASLEVTQQ QATQAEGQLL ELRKQSSQIQ NSACILASWV
SGKFSSLLQA LEIQHTTALR SIEVAKTQAL AQARDEEQRL RVHLEAVARH GCRIRELLEQ
VDEQTFLQES QLLQPPGPLG PLTPLQWDED QQLGDLKQLL SRLCGLLLEE GSHPGAPAKP
VDLAPVEAPG PLAPVPSTVC PLRRKLWQNY RNLTFDPVSA NRHFYLSRQD QQVKHCRQSR
GPGGPGSFEL WQVQCAQSFQ AGHHYWEVRA SDHSVTLGVS YPQLPRCRLG PHTDNIGRGP
CSWGLCVQED SLQAWHNGEA QRLPGVSGRL LGMDLDLASG CLTFYSLEPQ TQPLYTFHAL
FNQPLTPVFW LLEGRTLTLC HQPGAVFPLG PQEEVLS
//
