NS8_SARS2
ID NS8_SARS2 Reviewed; 121 AA.
AC P0DTC8;
DT 22-APR-2020, integrated into UniProtKB/Swiss-Prot.
DT 22-APR-2020, sequence version 1.
DT 03-AUG-2022, entry version 12.
DE RecName: Full=ORF8 protein;
DE Short=ORF8;
DE AltName: Full=Non-structural protein 8;
DE Short=ns8;
DE Flags: Precursor;
GN ORFNames=8;
OS Severe acute respiratory syndrome coronavirus 2 (2019-nCoV) (SARS-CoV-2).
OC Viruses; Riboviria; Orthornavirae; Pisuviricota; Pisoniviricetes;
OC Nidovirales; Cornidovirineae; Coronaviridae; Orthocoronavirinae;
OC Betacoronavirus; Sarbecovirus.
OX NCBI_TaxID=2697049;
OH NCBI_TaxID=9606; Homo sapiens (Human).
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RX PubMed=32015508; DOI=10.1038/s41586-020-2008-3;
RA Wu F., Zhao S., Yu B., Chen Y.-M., Wang W., Song Z.-G., Hu Y., Tao Z.-W.,
RA Tian J.-H., Pei Y.-Y., Yuan M.-L., Zhang Y.-L., Dai F.-H., Liu Y.,
RA Wang Q.-M., Zheng J.-J., Xu L., Holmes E.C., Zhang Y.-Z.;
RT "A new coronavirus associated with human respiratory disease in China.";
RL Nature 579:265-269(2020).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RC STRAIN=isolate 2019-nCoV_HKU-SZ-002a_2020;
RX PubMed=31986261; DOI=10.1016/s0140-6736(20)30154-9;
RA Chan J.F., Yuan S., Kok K.H., To K.K., Chu H., Yang J., Xing F., Liu J.,
RA Yip C.C., Poon R.W., Tsoi H.W., Lo S.K., Chan K.H., Poon V.K., Chan W.M.,
RA Ip J.D., Cai J.P., Cheng V.C., Chen H., Hui C.K., Yuen K.Y.;
RT "A familial cluster of pneumonia associated with the 2019 novel coronavirus
RT indicating person-to-person transmission: a study of a family cluster.";
RL Lancet 395:514-523(2020).
RN [3]
RP MISCELLANEOUS.
RX PubMed=32854725; DOI=10.1186/s12985-020-01402-1;
RA Michel C.J., Mayer C., Poch O., Thompson J.D.;
RT "Characterization of accessory genes in coronavirus genomes.";
RL Virol. J. 17:131-131(2020).
RN [4]
RP MISCELLANEOUS.
RX PubMed=32807944; DOI=10.1038/s41590-020-0773-7;
RA Hachim A., Kavian N., Cohen C.A., Chin A.W.H., Chu D.K.W., Mok C.K.P.,
RA Tsang O.T.Y., Yeung Y.C., Perera R.A.P.M., Poon L.L.M., Peiris J.S.M.,
RA Valkenburg S.A.;
RT "ORF8 and ORF3b antibodies are accurate serological markers of early and
RT late SARS-CoV-2 infection.";
RL Nat. Immunol. 21:1293-1301(2020).
RN [5]
RP INTERACTION WITH HUMAN IL17RA, AND SUBCELLULAR LOCATION.
RX PubMed=33060197; DOI=10.1126/science.abe9403;
RG QCRG Structural Biology Consortium;
RG Zoonomia Consortium;
RA Gordon D.E., Hiatt J., Bouhaddou M., Rezelj V.V., Ulferts S., Braberg H.,
RA Jureka A.S., Obernier K., Guo J.Z., Batra J., Kaake R.M., Weckstein A.R.,
RA Owens T.W., Gupta M., Pourmal S., Titus E.W., Cakir M., Soucheray M.,
RA McGregor M., Cakir Z., Jang G., O'Meara M.J., Tummino T.A., Zhang Z.,
RA Foussard H., Rojc A., Zhou Y., Kuchenov D., Huettenhain R., Xu J.,
RA Eckhardt M., Swaney D.L., Fabius J.M., Ummadi M., Tutuncuoglu B.,
RA Rathore U., Modak M., Haas P., Haas K.M., Naing Z.Z.C., Pulido E.H.,
RA Shi Y., Barrio-Hernandez I., Memon D., Petsalaki E., Dunham A.,
RA Marrero M.C., Burke D., Koh C., Vallet T., Silvas J.A., Azumaya C.M.,
RA Billesboelle C., Brilot A.F., Campbell M.G., Diallo A., Dickinson M.S.,
RA Diwanji D., Herrera N., Hoppe N., Kratochvil H.T., Liu Y., Merz G.E.,
RA Moritz M., Nguyen H.C., Nowotny C., Puchades C., Rizo A.N.,
RA Schulze-Gahmen U., Smith A.M., Sun M., Young I.D., Zhao J., Asarnow D.,
RA Biel J., Bowen A., Braxton J.R., Chen J., Chio C.M., Chio U.S.,
RA Deshpande I., Doan L., Faust B., Flores S., Jin M., Kim K., Lam V.L.,
RA Li F., Li J., Li Y.L., Li Y., Liu X., Lo M., Lopez K.E., Melo A.A.,
RA Moss F.R. III, Nguyen P., Paulino J., Pawar K.I., Peters J.K.,
RA Pospiech T.H. Jr., Safari M., Sangwan S., Schaefer K., Thomas P.V.,
RA Thwin A.C., Trenker R., Tse E., Tsui T.K.M., Wang F., Whitis N., Yu Z.,
RA Zhang K., Zhang Y., Zhou F., Saltzberg D., Hodder A.J., Shun-Shion A.S.,
RA Williams D.M., White K.M., Rosales R., Kehrer T., Miorin L., Moreno E.,
RA Patel A.H., Rihn S., Khalid M.M., Vallejo-Gracia A., Fozouni P.,
RA Simoneau C.R., Roth T.L., Wu D., Karim M.A., Ghoussaini M., Dunham I.,
RA Berardi F., Weigang S., Chazal M., Park J., Logue J., McGrath M.,
RA Weston S., Haupt R., Hastie C.J., Elliott M., Brown F., Burness K.A.,
RA Reid E., Dorward M., Johnson C., Wilkinson S.G., Geyer A., Giesel D.M.,
RA Baillie C., Raggett S., Leech H., Toth R., Goodman N., Keough K.C.,
RA Lind A.L., Klesh R.J., Hemphill K.R., Carlson-Stevermer J., Oki J.,
RA Holden K., Maures T., Pollard K.S., Sali A., Agard D.A., Cheng Y.,
RA Fraser J.S., Frost A., Jura N., Kortemme T., Manglik A., Southworth D.R.,
RA Stroud R.M., Alessi D.R., Davies P., Frieman M.B., Ideker T., Abate C.,
RA Jouvenet N., Kochs G., Shoichet B., Ott M., Palmarini M., Shokat K.M.,
RA Garcia-Sastre A., Rassen J.A., Grosse R., Rosenberg O.S., Verba K.A.,
RA Basler C.F., Vignuzzi M., Peden A.A., Beltrao P., Krogan N.J.;
RT "Comparative host-coronavirus protein interaction networks reveal pan-viral
RT disease mechanisms.";
RL Science 0:0-0(2020).
RN [6]
RP INTERACTION WITH HUMAN IL17RA, AND FUNCTION.
RX PubMed=33723527; DOI=10.1016/j.isci.2021.102293;
RA Lin X., Fu B., Yin S., Li Z., Liu H., Zhang H., Xing N., Wang Y., Xue W.,
RA Xiong Y., Zhang S., Zhao Q., Xu S., Zhang J., Wang P., Nian W., Wang X.,
RA Wu H.;
RT "Title: ORF8 contributes to cytokine storm during SARS-CoV-2 infection by
RT activating IL-17 pathway.";
RL IScience 1:102293-102293(2021).
RN [7]
RP VARIANT SER-84.
RX PubMed=32615316; DOI=10.1016/j.meegid.2020.104445;
RA Laha S., Chakraborty J., Das S., Manna S.K., Biswas S., Chatterjee R.;
RT "Characterizations of SARS-CoV-2 mutational profile, spike protein
RT stability and viral transmission.";
RL Infect. Genet. Evol. 85:104445-104445(2020).
RN [8]
RP VARIANT 28-HIS--ILE-121 DEL.
RC STRAIN=20B/501Y.V1, B.1.1.7, VOC-202012/01, and VUI-202012/01;
RX PubMed=33413740; DOI=10.2807/1560-7917.es.2020.26.1.2002106;
RA Leung K., Shum M.H., Leung G.M., Lam T.T., Wu J.T.;
RT "Early transmissibility assessment of the N501Y mutant strains of SARS-CoV-
RT 2 in the United Kingdom, October to November 2020.";
RL Eurosurveillance 26:0-0(2021).
RN [9]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=34177923; DOI=10.3389/fimmu.2021.679482;
RA Geng H., Subramanian S., Wu L., Bu H.F., Wang X., Du C., De Plaen I.G.,
RA Tan X.D.;
RT "SARS-CoV-2 ORF8 Forms Intracellular Aggregates and Inhibits IFNgamma-
RT Induced Antiviral Gene Expression in Human Lung Epithelial Cells.";
RL Front. Immunol. 12:679482-679482(2021).
RN [10]
RP FUNCTION, AND INTERACTION WITH HOST MHC-I.
RX PubMed=34021074; DOI=10.1073/pnas.2024202118;
RA Zhang Y., Chen Y., Li Y., Huang F., Luo B., Yuan Y., Xia B., Ma X.,
RA Yang T., Yu F., Liu J., Liu B., Song Z., Chen J., Yan S., Wu L., Pan T.,
RA Zhang X., Li R., Huang W., He X., Xiao F., Zhang J., Zhang H.;
RT "The ORF8 protein of SARS-CoV-2 mediates immune evasion through down-
RT regulating MHC-Iota.";
RL Proc. Natl. Acad. Sci. U.S.A. 118:1-12(2021).
RN [11]
RP FUNCTION, SUBCELLULAR LOCATION, HOMODIMERIZATION, MUTAGENESIS OF CYS-20 AND
RP ASN-78, DISULFIDE BOND, AND GLYCOSYLATION AT ASN-78.
RX PubMed=35157849; DOI=10.1016/j.jbc.2022.101724;
RA Matsuoka K., Imahashi N., Ohno M., Ode H., Nakata Y., Kubota M.,
RA Sugimoto A., Imahashi M., Yokomaku Y., Iwatani Y.;
RT "SARS-CoV-2 accessory protein ORF8 is secreted extracellularly as a
RT glycoprotein homodimer.";
RL J. Biol. Chem. 1:101724-101724(2022).
RN [12]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH HUMAN IL17RA, AND
RP MUTAGENESIS OF SER-24; TYR-42; VAL-62; ILE-71; ILE-76; LEU-84 AND GLU-106.
RX PubMed=35343786; DOI=10.1128/mbio.00402-22;
RA Wu X., Xia T., Shin W.J., Yu K.M., Jung W., Herrmann A., Foo S.S., Chen W.,
RA Zhang P., Lee J.S., Poo H., Comhair S.A.A., Jehi L., Choi Y.K., Ensser A.,
RA Jung J.U.;
RT "Viral Mimicry of Interleukin-17A by SARS-CoV-2 ORF8.";
RL MBio 1:e0040222-e0040222(2022).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (1.61 ANGSTROMS) OF 18-121, AND DISULFIDE BOND.
RA Nelson C.A., Hall P.D., Fremont D.H.;
RT "Crystal Structure of the SARS-CoV-2 ORF8 Protein.";
RL Submitted (AUG-2020) to the PDB data bank.
RN [14]
RP X-RAY CRYSTALLOGRAPHY (2.04 ANGSTROMS) OF 18-121, DISULFIDE BOND, AND
RP HOMODIMERIZATION.
RX PubMed=33361333; DOI=10.1073/pnas.2021785118;
RA Flower T.G., Buffalo C.Z., Hooy R.M., Allaire M., Ren X., Hurley J.H.;
RT "Structure of SARS-CoV-2 ORF8, a rapidly evolving immune evasion protein.";
RL Proc. Natl. Acad. Sci. U.S.A. 118:0-0(2021).
CC -!- FUNCTION: Plays a role in modulating the host immune response
CC (PubMed:31986261, PubMed:35343786). May act as a secreted virokine by
CC mimicking interleukin-17A (IL17A), and thereby binding to the IL17RA
CC receptor, leading to activation of the IL17 pathway and increased
CC secretion of pro-inflammatory factors (PubMed:35343786). Contributes to
CC the cytokine storm during SARS-CoV-2 infection (PubMed:33723527). May
CC act by down-regulating major histocompability complex class I (MHC-I)
CC at cell surface (PubMed:34021074, PubMed:35157849). May inhibit
CC expression of some members of the IFN-stimulated gene (ISG) family
CC including hosts IGF2BP1/ZBP1, MX1 and MX2, and DHX58 (PubMed:34177923).
CC {ECO:0000269|PubMed:33723527, ECO:0000269|PubMed:34021074,
CC ECO:0000269|PubMed:34177923, ECO:0000269|PubMed:35157849,
CC ECO:0000269|PubMed:35343786, ECO:0000303|PubMed:31986261}.
CC -!- SUBUNIT: Homodimer (PubMed:33361333, PubMed:35157849). Interacts with
CC host IL17RA (PubMed:33060197, PubMed:35343786). Interacts with host
CC IL17RC (PubMed:35343786). Interacts with host MHC-I (PubMed:34021074).
CC {ECO:0000269|PubMed:33060197, ECO:0000269|PubMed:33361333,
CC ECO:0000269|PubMed:33723527, ECO:0000269|PubMed:35157849,
CC ECO:0000269|PubMed:35343786}.
CC -!- INTERACTION:
CC P0DTC8; P0DTC8: 8; NbExp=3; IntAct=EBI-25475900, EBI-25475900;
CC P0DTC8; P01892: HLA-A; Xeno; NbExp=5; IntAct=EBI-25475900, EBI-2839473;
CC P0DTC8; P04439: HLA-A; Xeno; NbExp=3; IntAct=EBI-25475900, EBI-1042870;
CC P0DTC8; Q96F46: IL17RA; Xeno; NbExp=3; IntAct=EBI-25475900, EBI-5591258;
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:35157849,
CC ECO:0000269|PubMed:35343786}. Note=Its mRNA is expressed in cytoplasm
CC and the protein is secreted during a normal viral infection
CC (PubMed:35157849). Spliced when expressed from cDNA in nucleus
CC (PubMed:35157849). Splicing changes localization to host endosome
CC and/or cytoplasm (PubMed:33060197, PubMed:34177923). May also localize
CC in nucleus when fused with GFP (PubMed:34177923).
CC {ECO:0000269|PubMed:33060197, ECO:0000269|PubMed:34177923,
CC ECO:0000269|PubMed:35157849}.
CC -!- POLYMORPHISM: Variant B.1.1.7 is also called Variant Of Concern (VOC)
CC 202012/01, Variant Under Investigation (VUI) 202012/01, or 20B/501Y.V1.
CC {ECO:0000305|PubMed:33413740}.
CC -!- POLYMORPHISM: Variant Omicron/BA.1 and BA.2 belong to a lineage first
CC isolated in South Africa (November 2021). {ECO:0000305}.
CC -!- MISCELLANEOUS: Similar to some Bat coronavirus ns8 genes, but is
CC entirely different from SARS ns8a or Ns8b (Probable). Elicits strong
CC specific antibody response (PubMed:32807944).
CC {ECO:0000269|PubMed:32807944, ECO:0000305|PubMed:32854725}.
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DR EMBL; MN908947; QHD43422.1; -; Genomic_RNA.
DR EMBL; MN938384; -; NOT_ANNOTATED_CDS; Genomic_RNA.
DR RefSeq; YP_009724396.1; NC_045512.2.
DR PDB; 7JTL; X-ray; 2.04 A; A/B=18-121.
DR PDB; 7JX6; X-ray; 1.61 A; A/B=18-121.
DR PDBsum; 7JTL; -.
DR PDBsum; 7JX6; -.
DR SMR; P0DTC8; -.
DR BioGRID; 4383873; 905.
DR ComplexPortal; CPX-6147; SARS-CoV-2 ORF8 complex.
DR IntAct; P0DTC8; 129.
DR GeneID; 43740577; -.
DR KEGG; vg:43740577; -.
DR Reactome; R-HSA-448424; Interleukin-17 signaling.
DR Reactome; R-HSA-9705671; SARS-CoV-2 activates/modulates innate and adaptive immune responses.
DR Reactome; R-HSA-983170; Antigen Presentation: Folding, assembly and peptide loading of class I MHC.
DR PRO; PR:P0DTC8; -.
DR Proteomes; UP000464024; Genome.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:ComplexPortal.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0005764; C:lysosome; IDA:ComplexPortal.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0032688; P:negative regulation of interferon-beta production; IDA:ComplexPortal.
DR GO; GO:0002891; P:positive regulation of immunoglobulin mediated immune response; IDA:ComplexPortal.
DR GO; GO:0046776; P:suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I; IDA:ComplexPortal.
DR CDD; cd21641; ORF8-Ig_SARS-CoV-2-like; 1.
DR InterPro; IPR022722; ORF8_betacoronavirus.
DR InterPro; IPR044391; ORF8_SARS-CoV-2-like.
DR Pfam; PF12093; bCoV_NS8; 1.
DR PROSITE; PS51964; SARS_ORF8_IG; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Disulfide bond;
KW Evasion of host immunity by viral interleukin-like protein; Glycoprotein;
KW Host-virus interaction; Reference proteome; Secreted; Signal;
KW Viral immunoevasion.
FT SIGNAL 1..15
FT /evidence="ECO:0000255"
FT CHAIN 16..121
FT /note="ORF8 protein"
FT /id="PRO_0000449655"
FT DOMAIN 19..121
FT /note="SARS ORF8 Ig-like"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01309"
FT CARBOHYD 78
FT /note="N-linked (GlcNAc...) (complex) asparagine; by host"
FT /evidence="ECO:0000269|PubMed:35157849"
FT DISULFID 20
FT /note="Interchain"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01309,
FT ECO:0000269|PubMed:33361333, ECO:0000269|PubMed:35157849"
FT DISULFID 25..90
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01309,
FT ECO:0000269|PubMed:33361333, ECO:0000269|Ref.13"
FT DISULFID 37..102
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01309,
FT ECO:0000269|PubMed:33361333, ECO:0000269|Ref.13"
FT DISULFID 61..83
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01309,
FT ECO:0000269|PubMed:33361333, ECO:0000269|Ref.13"
FT VARIANT 2
FT /note="K -> Q (in strain: Theta/P.3)"
FT /evidence="ECO:0000305"
FT VARIANT 11
FT /note="T -> I (in strain: Iota/B.1.526)"
FT /evidence="ECO:0000305"
FT VARIANT 11
FT /note="T -> K (in strain: Mu/B.1.621)"
FT /evidence="ECO:0000305"
FT VARIANT 28..121
FT /note="Missing (in strain: B.1.1.7)"
FT /evidence="ECO:0000305|PubMed:33413740"
FT VARIANT 38
FT /note="P -> S (in strain: Mu/B.1.621)"
FT /evidence="ECO:0000305"
FT VARIANT 84
FT /note="L -> S (in strain: Omicron/BA.1, Omicron/BA.2,
FT Omicron/BA.2.12.1, Omicron/BA.4, Omicron/BA.5)"
FT /evidence="ECO:0000305, ECO:0000305|PubMed:32615316"
FT VARIANT 92
FT /note="E -> K (in strain: Gamma/P.1)"
FT /evidence="ECO:0000305"
FT VARIANT 119
FT /note="D -> I (in strain: Delta/B.1.617.2)"
FT /evidence="ECO:0000305"
FT VARIANT 120..121
FT /note="Missing (in strain: Delta/B.1.617.2)"
FT /evidence="ECO:0000305"
FT MUTAGEN 20
FT /note="C->A: Complete loss of dimerization."
FT /evidence="ECO:0000269|PubMed:35157849"
FT MUTAGEN 24
FT /note="S->L: Partial loss of hIL-17RC binding."
FT /evidence="ECO:0000269|PubMed:35343786"
FT MUTAGEN 42
FT /note="Y->H: Complete loss of hIL-17RA binding."
FT /evidence="ECO:0000269|PubMed:35343786"
FT MUTAGEN 62
FT /note="V->L: Partial loss of hIL-17RC binding."
FT /evidence="ECO:0000269|PubMed:35343786"
FT MUTAGEN 71
FT /note="I->D: Complete loss of hIL-17RC binding."
FT /evidence="ECO:0000269|PubMed:35343786"
FT MUTAGEN 76
FT /note="I->D: Complete loss of hIL-17RC binding."
FT /evidence="ECO:0000269|PubMed:35343786"
FT MUTAGEN 78
FT /note="N->D: Complete loss of N-glycosylation and of
FT secretion."
FT /evidence="ECO:0000269|PubMed:35157849"
FT MUTAGEN 84
FT /note="L->S: Complete loss of IL17RA binding."
FT /evidence="ECO:0000269|PubMed:35343786"
FT MUTAGEN 106
FT /note="E->P: Complete loss of hIL-17RA binding."
FT /evidence="ECO:0000269|PubMed:35343786"
FT STRAND 19..25
FT /evidence="ECO:0007829|PDB:7JX6"
FT STRAND 29..32
FT /evidence="ECO:0007829|PDB:7JX6"
FT STRAND 41..49
FT /evidence="ECO:0007829|PDB:7JX6"
FT STRAND 57..70
FT /evidence="ECO:0007829|PDB:7JX6"
FT STRAND 80..82
FT /evidence="ECO:0007829|PDB:7JX6"
FT TURN 83..86
FT /evidence="ECO:0007829|PDB:7JX6"
FT STRAND 87..91
FT /evidence="ECO:0007829|PDB:7JX6"
FT STRAND 96..105
FT /evidence="ECO:0007829|PDB:7JX6"
FT STRAND 112..120
FT /evidence="ECO:0007829|PDB:7JX6"
SQ SEQUENCE 121 AA; 13831 MW; 912AD9E147A64907 CRC64;
MKFLVFLGII TTVAAFHQEC SLQSCTQHQP YVVDDPCPIH FYSKWYIRVG ARKSAPLIEL
CVDEAGSKSP IQYIDIGNYT VSCLPFTINC QEPKLGSLVV RCSFYEDFLE YHDVRVVLDF
I
