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   10-FEB-2021, entry version 6.
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.
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, AND MUTAGENESIS OF MET-58.
RX   PubMed=33097660; DOI=10.1101/2020.05.06.081497;
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. 0:0-0(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).
CC   -!- FUNCTION: Disrupts cell nuclear import complex formation by tethering
CC       karyopherin alpha 2 and karyopherin beta 1 to the membrane. Retention
CC       of import factors at the ER/Golgi membrane leads to a loss of transport
CC       into the nucleus. Thereby prevents STAT1 nuclear translocation in
CC       response to interferon signaling, thus blocking the expression of
CC       interferon stimulated genes (ISGs) that display multiple antiviral
CC       activities (PubMed:33097660). Suppresses IFN-beta production possibly
CC       by blocking IRF3 nuclear translocation (PubMed:32979938).
CC       {ECO:0000269|PubMed:32979938, ECO:0000269|PubMed:33097660}.
CC   -!- SUBUNIT: Interacts with host KPNA2; this interaction may inhibit IFN-
CC       beta production by blocking IRF3 nuclear translocation
CC       (PubMed:32979938). Associates (via C-terminus) with the NUP98-RAE1
CC       complex; this interaction disrupts the host nuclear import
CC       (PubMed:33097660). May interact with nsp8 (By similarity). Interacts
CC       with protein ORF9b (By similarity). {ECO:0000250|UniProtKB:P59634,
CC       ECO:0000269|PubMed:32979938, ECO:0000269|PubMed:33097660}.
CC   -!- SUBCELLULAR LOCATION: Host endoplasmic reticulum membrane
CC       {ECO:0000250|UniProtKB:P59634, ECO:0000269|PubMed:33060197}. Host Golgi
CC       apparatus membrane {ECO:0000250|UniProtKB:P59634,
CC       ECO:0000269|PubMed:33060197}. Host cytoplasm
CC       {ECO:0000250|UniProtKB:P59634}. Note=Localizes to virus-induced
CC       vesicular structures called double membrane vesicles.
CC       {ECO:0000250|UniProtKB:P59634}.
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   BioGRID; 4383870; 566.
DR   IntAct; P0DTC6; 21.
DR   GeneID; 43740572; -.
DR   KEGG; vg:43740572; -.
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:0009405; P:pathogenesis; IEA:UniProtKB-KW.
DR   InterPro; IPR022736; NS6_bCoV.
DR   Pfam; PF12133; bCoV_NS6; 1.
PE   1: Evidence at protein level;
KW   Host cytoplasm; 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   Membrane; Reference proteome; Viral immunoevasion; Virulence.
FT   CHAIN           1..61
FT                   /note="ORF6 protein"
FT                   /id="PRO_0000449653"
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"
SQ   SEQUENCE   61 AA;  7273 MW;  B21BD303F59A1D0A CRC64;
     MFHLVDFQVT IAEILLIIMR TFKVSIWNLD YIINLIIKNL SKSLTENKYS QLDEEQPMEI
     D
//