ID NS6_SARS2 Reviewed; 61 AA.
AC P0DTC6;
DT 22-APR-2020, integrated into UniProtKB/Swiss-Prot.
DT 22-APR-2020, sequence version 1.
DT 02-OCT-2024, entry version 23.
DE RecName: Full=ORF6 protein;
DE Short=ORF6;
DE AltName: Full=Accessory protein 6;
DE AltName: Full=Non-structural protein 6;
DE Short=ns6;
DE AltName: Full=Protein X3;
GN ORFNames=6;
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;
OC Severe acute respiratory syndrome coronavirus.
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 FUNCTION, AND INTERACTION WITH HOST KPNA2.
RX PubMed=32979938; DOI=10.1016/j.celrep.2020.108234;
RA Xia H., Cao Z., Xie X., Zhang X., Chen J.Y., Wang H., Menachery V.D.,
RA Rajsbaum R., Shi P.Y.;
RT "Evasion of Type I Interferon by SARS-CoV-2.";
RL Cell Rep. 33:108234-108234(2020).
RN [3]
RP FUNCTION, INTERACTION WITH HUMAN NUP98-RAE1 COMPLEX, AND MUTAGENESIS OF
RP MET-58.
RX PubMed=33097660; DOI=10.1073/pnas.2016650117;
RA Miorin L., Kehrer T., Sanchez-Aparicio M.T., Zhang K., Cohen P.,
RA Patel R.S., Cupic A., Makio T., Mei M., Moreno E., Danziger O., White K.M.,
RA Rathnasinghe R., Uccellini M., Gao S., Aydillo T., Mena I., Yin X.,
RA Martin-Sancho L., Krogan N.J., Chanda S.K., Schotsaert M., Wozniak R.W.,
RA Ren Y., Rosenberg B.R., Fontoura B.M.A., Garcia-Sastre A.;
RT "SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize
RT interferon signaling.";
RL Proc. Natl. Acad. Sci. U.S.A. 117:28344-28354(2020).
RN [4]
RP 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 [5]
RP FUNCTION, AND INTERACTION WITH HUMAN NUP98-RAE1 COMPLEX.
RX PubMed=33360543; DOI=10.1016/j.bbrc.2020.11.115;
RA Kato K., Ikliptikawati D.K., Kobayashi A., Kondo H., Lim K., Hazawa M.,
RA Wong R.W.;
RT "Overexpression of SARS-CoV-2 protein ORF6 dislocates RAE1 and NUP98 from
RT the nuclear pore complex.";
RL Biochem. Biophys. Res. Commun. 536:59-66(2021).
RN [6]
RP FUNCTION, INTERACTION WITH HUMAN NUP98-RAE1 COMPLEX, AND MUTAGENESIS OF
RP 1-MET--LEU-16; 22-PHE--ASP-30; 38-LYS--ASP-61; 50-SER--ASP-61; MET-58 AND
RP ASP-61.
RX PubMed=33849972; DOI=10.1128/mbio.00065-21;
RA Addetia A., Lieberman N.A.P., Phung Q., Hsiang T.Y., Xie H.,
RA Roychoudhury P., Shrestha L., Loprieno M.A., Huang M.L., Gale M. Jr.,
RA Jerome K.R., Greninger A.L.;
RT "SARS-CoV-2 ORF6 Disrupts Bidirectional Nucleocytoplasmic Transport through
RT Interactions with Rae1 and Nup98.";
RL MBio 12:0-0(2021).
RN [7]
RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF 18-ILE--VAL-24.
RX PubMed=35187564; DOI=10.1242/jcs.259666;
RA Wong H.T., Cheung V., Salamango D.J.;
RT "Decoupling SARS-CoV-2 ORF6 localization and interferon antagonism.";
RL J. Cell Sci. 0:0-0(2022).
RN [8] {ECO:0007744|PDB:7VPH}
RP X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) OF 41-61, INTERACTION WITH HOST
RP RAE1-NUP98, AND MUTAGENESIS OF MET-58.
RX PubMed=35096974; DOI=10.3389/fmolb.2021.813248;
RA Li T., Wen Y., Guo H., Yang T., Yang H., Ji X.;
RT "Molecular mechanism of SARS-CoVs Orf6 targeting the Rae1-Nup98 complex to
RT compete with mRNA nuclear export.";
RL Front. Mol. Biosci. 8:813248-813248(2022).
CC -!- FUNCTION: Disrupts bidirectional nucleocytoplasmic transport by
CC interacting with the host RAE1-NUP98 complex (PubMed:33360543,
CC PubMed:33849972). Disrupts cell nuclear import complex formation by
CC tethering karyopherin alpha 2 and karyopherin beta 1 to the membrane
CC (PubMed:32979938). Retention of import factors at the ER/Golgi membrane
CC leads to a loss of transport into the nucleus (By similarity). Prevents
CC STAT1 nuclear translocation in response to interferon signaling, thus
CC blocking the expression of interferon stimulated genes (ISGs) that
CC display multiple antiviral activities (PubMed:33097660). Suppresses
CC IFN-beta production possibly by blocking IRF3 nuclear translocation
CC (PubMed:32979938). Might induce accumulation of host HNRNPA1
CC (PubMed:33360543). {ECO:0000250|UniProtKB:P59634,
CC ECO:0000269|PubMed:32979938, ECO:0000269|PubMed:33097660,
CC ECO:0000269|PubMed:33360543, ECO:0000269|PubMed:33849972}.
CC -!- FUNCTION: May play a role in viral double membrane vesicles networks to
CC enhance viral replication. {ECO:0000269|PubMed:35187564}.
CC -!- SUBUNIT: Interacts (via C-terminus) with host RAE1 in the NUP98-RAE1
CC complex (PubMed:35096974); this interaction disrupts the host nuclear
CC import (PubMed:33097660, PubMed:33360543, PubMed:33849972,
CC PubMed:35096974). Interacts with host KPNA2; this interaction may
CC inhibit IFN-beta production by blocking IRF3 nuclear translocation
CC (PubMed:32979938). {ECO:0000269|PubMed:32979938,
CC ECO:0000269|PubMed:33097660, ECO:0000269|PubMed:33360543,
CC ECO:0000269|PubMed:33849972, ECO:0000269|PubMed:35096974}.
CC -!- INTERACTION:
CC P0DTC6; O95870: ABHD16A; Xeno; NbExp=3; IntAct=EBI-25475897, EBI-348517;
CC P0DTC6; Q15041: ARL6IP1; Xeno; NbExp=3; IntAct=EBI-25475897, EBI-714543;
CC P0DTC6; P52292: KPNA2; Xeno; NbExp=2; IntAct=EBI-25475897, EBI-349938;
CC P0DTC6; P52948: NUP98; Xeno; NbExp=11; IntAct=EBI-25475897, EBI-295727;
CC P0DTC6; O75360: PROP1; Xeno; NbExp=3; IntAct=EBI-25475897, EBI-9027467;
CC P0DTC6; P78406: RAE1; Xeno; NbExp=11; IntAct=EBI-25475897, EBI-724495;
CC P0DTC6; Q96HR9: REEP6; Xeno; NbExp=4; IntAct=EBI-25475897, EBI-750345;
CC P0DTC6; Q9UMX0: UBQLN1; Xeno; NbExp=3; IntAct=EBI-25475897, EBI-741480;
CC P0DTC6; Q9UHD9: UBQLN2; Xeno; NbExp=4; IntAct=EBI-25475897, EBI-947187;
CC P0DTC6; Q9NYU1: UGGT2; Xeno; NbExp=3; IntAct=EBI-25475897, EBI-1054215;
CC -!- SUBCELLULAR LOCATION: Host endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:33060197, ECO:0000269|PubMed:35187564}; Peripheral
CC membrane protein {ECO:0000269|PubMed:35187564}. Host Golgi apparatus
CC membrane {ECO:0000269|PubMed:33060197, ECO:0000269|PubMed:35187564};
CC Peripheral membrane protein {ECO:0000269|PubMed:35187564}.
CC Note=Localizes to virus-induced vesicular structures called double
CC membrane vesicles.
CC -!- POLYMORPHISM: Variant Omicron/BQ.1.1 belongs to a lineage first
CC isolated in Nigeria (November 2022). {ECO:0000305}.
CC -!- POLYMORPHISM: Variant Omicron/XBB.1.5 belongs to a lineage first
CC isolated in United States (November 2022). It is the result of
CC recombination between omicron BJ.1 and BM.1.1. Moreover XBB.1.5 do not
CC express ORF8. {ECO:0000305}.
CC -!- POLYMORPHISM: Variant Omicron/BA.1 and BA.2 belong to a lineage first
CC isolated in South Africa (November 2021). {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the coronaviruses accessory protein 6 family.
CC {ECO:0000305}.
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DR EMBL; MN908947; QHD43420.1; -; Genomic_RNA.
DR RefSeq; YP_009724394.1; NC_045512.2.
DR PDB; 7F60; X-ray; 2.85 A; E/F=1-61.
DR PDB; 7VPH; X-ray; 2.80 A; I/J/K/X=41-61.
DR PDBsum; 7F60; -.
DR PDBsum; 7VPH; -.
DR SMR; P0DTC6; -.
DR BioGRID; 4383870; 1182.
DR IntAct; P0DTC6; 111.
DR MINT; P0DTC6; -.
DR iPTMnet; P0DTC6; -.
DR GeneID; 43740572; -.
DR AGR; RefSeq:YP_009724394; -.
DR Reactome; R-HSA-9705671; SARS-CoV-2 activates/modulates innate and adaptive immune responses.
DR Reactome; R-HSA-9727281; Translation of Accessory Proteins.
DR SIGNOR; P0DTC6; -.
DR PRO; PR:P0DTC6; -.
DR Proteomes; UP000464024; Genome.
DR GO; GO:0044167; C:host cell endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0044178; C:host cell Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016020; C:membrane; IEA:UniProtKB-KW.
DR GO; GO:0005643; C:nuclear pore; IDA:UniProt.
DR GO; GO:0140311; F:protein sequestering activity; IDA:UniProt.
DR GO; GO:0039548; P:symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of IRF3 activity; IDA:UniProt.
DR GO; GO:0039563; P:symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT1 activity; IEA:UniProtKB-KW.
DR GO; GO:0039564; P:symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT2 activity; IEA:UniProtKB-KW.
DR GO; GO:0039502; P:symbiont-mediated suppression of host type I interferon-mediated signaling pathway; IEA:UniProtKB-KW.
DR GO; GO:0019049; P:virus-mediated perturbation of host defense response; IEA:UniProtKB-KW.
DR InterPro; IPR022736; NS6_bCoV.
DR Pfam; PF12133; bCoV_NS6; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Host endoplasmic reticulum; Host Golgi apparatus;
KW Host membrane; Host-virus interaction;
KW Inhibition of host innate immune response by virus;
KW Inhibition of host interferon signaling pathway by virus;
KW Inhibition of host STAT1 by virus; Inhibition of host STAT2 by virus;
KW Interferon antiviral system evasion; Membrane; Reference proteome;
KW Viral immunoevasion; Virulence.
FT CHAIN 1..61
FT /note="ORF6 protein"
FT /id="PRO_0000449653"
FT REGION 18..24
FT /note="Important for host Golgi localization"
FT /evidence="ECO:0000269|PubMed:35187564"
FT VARIANT 2
FT /note="F -> H (in strain: Eta/B.1.525)"
FT /evidence="ECO:0000305"
FT VARIANT 3
FT /note="Missing (in strain: Eta/B.1.525)"
FT /evidence="ECO:0000305"
FT VARIANT 61
FT /note="D -> L (in strain: Omicron/BA.2, Omicron/BA.2.12.1,
FT Omicron/BA.2.75, Omicron/BA.4, Omicron/BQ.1.1, Omicron/
FT XBB.1.5, Omicron/EG.5.1)"
FT /evidence="ECO:0000305"
FT MUTAGEN 1..16
FT /note="Missing: Retains interaction with human NUP98-RAE1
FT complex. Increases down-regulation of protein expression of
FT newly transcribed genes in host cell."
FT /evidence="ECO:0000269|PubMed:33849972"
FT MUTAGEN 18..24
FT /note="IMRTFKV->AAAAAAA: Complete loss of Golgi
FT localization."
FT /evidence="ECO:0000269|PubMed:35187564"
FT MUTAGEN 18..24
FT /note="Missing: Complete loss of Golgi localization."
FT /evidence="ECO:0000269|PubMed:35187564"
FT MUTAGEN 22..30
FT /note="Missing: Retains interaction with human NUP98-RAE1
FT complex. Increases down-regulation of protein expression of
FT newly transcribed genes in host cell."
FT /evidence="ECO:0000269|PubMed:33849972"
FT MUTAGEN 38..61
FT /note="Missing: Loss of interaction with human NUP98-RAE1
FT complex which suppresses the down-regulation of protein
FT expression of newly transcribed genes in the host cell."
FT /evidence="ECO:0000269|PubMed:33849972"
FT MUTAGEN 50..61
FT /note="Missing: Loss of interaction with human NUP98-RAE1
FT complex which suppresses the down-regulation of protein
FT expression of newly transcribed genes in the host cell."
FT /evidence="ECO:0000269|PubMed:33849972"
FT MUTAGEN 58
FT /note="M->A: Loss of interaction with human NUP98-RAE1
FT complex which suppresses the mRNA accumulation in the
FT nucleus, the down-regulation of protein expression of newly
FT transcribed genes in the host cell and blockade on nuclear
FT import on a broad range of host factors."
FT /evidence="ECO:0000269|PubMed:33849972,
FT ECO:0000269|PubMed:35096974"
FT MUTAGEN 58
FT /note="M->R: Complete loss of binding to the NUP98-RAE1
FT complex and IFN antagonistic function."
FT /evidence="ECO:0000269|PubMed:33097660,
FT ECO:0000269|PubMed:35096974"
FT MUTAGEN 61
FT /note="D->DYP: Does not affect repression of reporter
FT protein expression."
FT /evidence="ECO:0000269|PubMed:33849972"
SQ SEQUENCE 61 AA; 7273 MW; B21BD303F59A1D0A CRC64;
MFHLVDFQVT IAEILLIIMR TFKVSIWNLD YIINLIIKNL SKSLTENKYS QLDEEQPMEI
D
//