NS1_I34A1
ID NS1_I34A1 Reviewed; 230 AA.
AC P03496; Q20N32; Q67267; Q71QT3;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 21-JUL-1986, sequence version 1.
DT 23-FEB-2022, entry version 145.
DE RecName: Full=Non-structural protein 1 {ECO:0000255|HAMAP-Rule:MF_04066};
DE Short=NS1 {ECO:0000255|HAMAP-Rule:MF_04066};
DE AltName: Full=NS1A {ECO:0000255|HAMAP-Rule:MF_04066};
GN Name=NS {ECO:0000255|HAMAP-Rule:MF_04066};
OS Influenza A virus (strain A/Puerto Rico/8/1934 H1N1).
OC Viruses; Riboviria; Orthornavirae; Negarnaviricota; Polyploviricotina;
OC Insthoviricetes; Articulavirales; Orthomyxoviridae; Alphainfluenzavirus.
OX NCBI_TaxID=211044;
OH NCBI_TaxID=8782; Aves.
OH NCBI_TaxID=9606; Homo sapiens (Human).
OH NCBI_TaxID=9823; Sus scrofa (Pig).
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RX PubMed=7465426; DOI=10.1093/nar/8.23.5845;
RA Baez M., Taussig R., Zazra J.J., Young J.F., Palese P., Reisfeld A.,
RA Skalka A.M.;
RT "Complete nucleotide sequence of the influenza A/PR/8/34 virus NS gene and
RT comparison with the NS genes of the A/Udorn/72 and A/FPV/Rostock/34
RT strains.";
RL Nucleic Acids Res. 8:5845-5858(1980).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RX PubMed=11779399; DOI=10.1098/rstb.2001.0979;
RA Schickli J.H., Flandorfer A., Nakaya T., Martinez-Sobrido L.,
RA Garcia-Sastre A., Palese P.;
RT "Plasmid-only rescue of influenza A virus vaccine candidates.";
RL Philos. Trans. R. Soc. Lond., B, Biol. Sci. 356:1965-1973(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC RNA], AND REVERSE GENETICS.
RX PubMed=15163504; DOI=10.1016/j.virusres.2004.02.028;
RA de Wit E., Spronken M.I.J., Bestebroer T.M., Rimmelzwaan G.F.,
RA Osterhaus A.D.M.E., Fouchier R.A.M.;
RT "Efficient generation and growth of influenza virus A/PR/8/34 from eight
RT cDNA fragments.";
RL Virus Res. 103:155-161(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RA Ghedin E., Spiro D., Miller N., Zaborsky J., Feldblyum T., Subbu V.,
RA Shumway M., Sparenborg J., Groveman L., Halpin R., Sitz J., Koo H.,
RA Salzberg S.L., Webster R.G., Hoffmann E., Krauss S., Naeve C., Bao Y.,
RA Bolotov P., Dernovoy D., Kiryutin B., Lipman D.J., Tatusova T.;
RT "The NIAID influenza genome sequencing project.";
RL Submitted (MAR-2006) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP REVIEW.
RX PubMed=12758165; DOI=10.1016/s0042-6822(03)00119-3;
RA Krug R.M., Yuan W., Noah D.L., Latham A.G.;
RT "Intracellular warfare between human influenza viruses and human cells: the
RT roles of the viral NS1 protein.";
RL Virology 309:181-189(2003).
RN [6]
RP INTERACTION WITH HUMAN TRIM25, AND MUTAGENESIS OF ARG-38; LYS-41; GLU-96
RP AND GLU-97.
RX PubMed=19454348; DOI=10.1016/j.chom.2009.04.006;
RA Gack M.U., Albrecht R.A., Urano T., Inn K.-S., Huang I.-C., Carnero E.,
RA Farzan M., Inoue S., Jung J.U., Garcia-Sastre A.;
RT "Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade
RT recognition by the host viral RNA sensor RIG-I.";
RL Cell Host Microbe 5:439-449(2009).
RN [7]
RP ISGYLATION AT LYS-20; LYS-41; LYS-108; LYS-110; LYS-126; LYS-217 AND
RP LYS-219, AND MUTAGENESIS OF LYS-20; LYS-41; LYS-108; LYS-110; LYS-126;
RP LYS-217 AND LYS-219.
RX PubMed=20385878; DOI=10.4049/jimmunol.0903588;
RA Tang Y., Zhong G., Zhu L., Liu X., Shan Y., Feng H., Bu Z., Chen H.,
RA Wang C.;
RT "Herc5 attenuates influenza A virus by catalyzing ISGylation of viral NS1
RT protein.";
RL J. Immunol. 184:5777-5790(2010).
CC -!- FUNCTION: Prevents the establishment of the cellular antiviral state by
CC inhibiting TRIM25-mediated DDX58 ubiquitination, which normally
CC triggers the antiviral transduction signal that leads to the activation
CC of type I IFN genes by transcription factors IRF3 and IRF7. Prevents
CC human EIF2AK2/PKR activation, either by binding double-strand RNA, or
CC by interacting directly with EIF2AK2/PKR. This function may be
CC important at the very beginning of the infection, when NS1 is mainly
CC present in the cytoplasm. Also binds poly(A) and U6 snRNA.
CC {ECO:0000255|HAMAP-Rule:MF_04066}.
CC -!- FUNCTION: Inhibits post-transcriptional processing of cellular pre-
CC mRNA, by binding and inhibiting two cellular proteins that are required
CC for the 3'-end processing of cellular pre-mRNAs: the 30 kDa cleavage
CC and polyadenylation specificity factor/CPSF4 and the poly(A)-binding
CC protein 2/PABPN1. In turn, unprocessed 3' end pre-mRNAs accumulate in
CC the host nucleus and are no longer exported to the cytoplasm. Cellular
CC protein synthesis is thereby shut off very early after virus infection.
CC Viral protein synthesis is not affected by the inhibition of the
CC cellular 3' end processing machinery because the poly(A) tails of viral
CC mRNAs are produced by the viral polymerase through a stuttering
CC mechanism. {ECO:0000255|HAMAP-Rule:MF_04066}.
CC -!- SUBUNIT: Homodimer. Interacts with host TRIM25 (via coiled coil); this
CC interaction specifically inhibits TRIM25 multimerization and TRIM25-
CC mediated DDX58 CARD ubiquitination. Interacts with human EIF2AK2/PKR,
CC CPSF4, IVNS1ABP and PABPN1. {ECO:0000255|HAMAP-Rule:MF_04066}.
CC -!- INTERACTION:
CC P03496; P03496: NS; NbExp=4; IntAct=EBI-2547442, EBI-2547442;
CC P03496; P55265: ADAR; Xeno; NbExp=8; IntAct=EBI-2547442, EBI-2462104;
CC P03496; Q12906: ILF3; Xeno; NbExp=3; IntAct=EBI-2547442, EBI-78756;
CC P03496; P27986: PIK3R1; Xeno; NbExp=6; IntAct=EBI-2547442, EBI-79464;
CC P03496; O00459: PIK3R2; Xeno; NbExp=13; IntAct=EBI-2547442, EBI-346930;
CC P03496; O75569: PRKRA; Xeno; NbExp=3; IntAct=EBI-2547442, EBI-713955;
CC P03496; O95793: STAU1; Xeno; NbExp=6; IntAct=EBI-2547442, EBI-358174;
CC P03496; Q14258: TRIM25; Xeno; NbExp=3; IntAct=EBI-2547442, EBI-2341129;
CC -!- SUBCELLULAR LOCATION: Host nucleus {ECO:0000255|HAMAP-Rule:MF_04066}.
CC Host cytoplasm {ECO:0000255|HAMAP-Rule:MF_04066}. Note=In uninfected,
CC transfected cells, NS1 is localized in the nucleus. Only in virus
CC infected cells, the nuclear export signal is unveiled, presumably by a
CC viral protein, and a fraction of NS1 is exported in the cytoplasm.
CC {ECO:0000255|HAMAP-Rule:MF_04066}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=NS1;
CC IsoId=P03496-1; Sequence=Displayed;
CC Name=NEP; Synonyms=NS2;
CC IsoId=P03508-1; Sequence=External;
CC -!- DOMAIN: The dsRNA-binding region is required for suppression of RNA
CC silencing. {ECO:0000255|HAMAP-Rule:MF_04066}.
CC -!- PTM: Upon interferon induction, ISGylated via host HERC5; this results
CC in the impairment of NS1 interaction with RNA targets due to its
CC inability to form homodimers and to interact with host EIF2AK2/PKR.
CC There are two ISGylated forms: one form is ISGylated at Lys-20, Lys-41,
CC Lys-217, and Lys-219, and another one at Lys-108, Lys-110, and Lys-126,
CC they represent band I and II respectively. Lys-126 and Lys-217 are
CC critical for host antiviral response in vivo. {ECO:0000255|HAMAP-
CC Rule:MF_04066, ECO:0000269|PubMed:20385878}.
CC -!- SIMILARITY: Belongs to the influenza A viruses NS1 family.
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DR EMBL; V01104; CAA24292.1; ALT_SEQ; Genomic_RNA.
DR EMBL; J02150; AAA43536.1; -; Genomic_RNA.
DR EMBL; AF389122; AAM75163.1; -; Genomic_RNA.
DR EMBL; EF467817; ABO21703.1; -; Genomic_RNA.
DR EMBL; CY009448; ABD77680.1; -; Genomic_RNA.
DR RefSeq; NP_040984.1; NC_002020.1.
DR PDB; 2GX9; X-ray; 2.10 A; A/B=79-207.
DR PDB; 2ZKO; X-ray; 1.70 A; A/B=1-70.
DR PDB; 3L4Q; X-ray; 2.30 A; A/B=73-230.
DR PDB; 3O9Q; X-ray; 2.50 A; A/B=79-230.
DR PDB; 3O9R; X-ray; 2.00 A; A/B=79-230.
DR PDB; 3O9S; X-ray; 2.48 A; A/B=79-230.
DR PDB; 3O9T; X-ray; 2.20 A; A/B=79-230.
DR PDB; 3O9U; X-ray; 3.20 A; A/B/C/D/E/F/G/H=79-230.
DR PDB; 3RVC; X-ray; 1.80 A; A=79-230.
DR PDB; 5NT1; X-ray; 2.82 A; B/F/J=80-230.
DR PDB; 5NT2; X-ray; 4.26 A; C/D/E/F=1-230.
DR PDBsum; 2GX9; -.
DR PDBsum; 2ZKO; -.
DR PDBsum; 3L4Q; -.
DR PDBsum; 3O9Q; -.
DR PDBsum; 3O9R; -.
DR PDBsum; 3O9S; -.
DR PDBsum; 3O9T; -.
DR PDBsum; 3O9U; -.
DR PDBsum; 3RVC; -.
DR PDBsum; 5NT1; -.
DR PDBsum; 5NT2; -.
DR SMR; P03496; -.
DR DIP; DIP-29081N; -.
DR IntAct; P03496; 222.
DR MINT; P03496; -.
DR ChEMBL; CHEMBL4523164; -.
DR GeneID; 956533; -.
DR KEGG; vg:956533; -.
DR Reactome; R-HSA-1169408; ISG15 antiviral mechanism.
DR Reactome; R-HSA-168276; NS1 Mediated Effects on Host Pathways.
DR Reactome; R-HSA-168315; Inhibition of Host mRNA Processing and RNA Silencing.
DR Reactome; R-HSA-168888; Inhibition of IFN-beta.
DR Reactome; R-HSA-169131; Inhibition of PKR.
DR Reactome; R-HSA-192823; Viral mRNA Translation.
DR Reactome; R-HSA-5213460; RIPK1-mediated regulated necrosis.
DR Reactome; R-HSA-9686347; Microbial modulation of RIPK1-mediated regulated necrosis.
DR EvolutionaryTrace; P03496; -.
DR Proteomes; UP000009255; Genome.
DR Proteomes; UP000116373; Genome.
DR Proteomes; UP000170967; Genome.
DR GO; GO:0030430; C:host cell cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0042025; C:host cell nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0030291; F:protein serine/threonine kinase inhibitor activity; IEA:UniProtKB-KW.
DR GO; GO:0003723; F:RNA binding; IEA:UniProtKB-KW.
DR GO; GO:0039524; P:suppression by virus of host mRNA processing; IEA:UniProtKB-KW.
DR GO; GO:0039580; P:suppression by virus of host PKR signaling; IEA:UniProtKB-KW.
DR GO; GO:0039502; P:suppression by virus of host type I interferon-mediated signaling pathway; IEA:UniProtKB-KW.
DR GO; GO:0039540; P:suppression by virus of host viral-induced cytoplasmic pattern recognition receptor signaling pathway via inhibition of host RIG-I activity; IEA:UniProtKB-KW.
DR Gene3D; 3.30.420.330; -; 1.
DR HAMAP; MF_04066; INFV_NS1; 1.
DR InterPro; IPR004208; NS1.
DR InterPro; IPR000256; NS1A.
DR InterPro; IPR038064; NS1A_effect_dom-like_sf.
DR InterPro; IPR009068; S15_NS1_RNA-bd.
DR Pfam; PF00600; Flu_NS1; 1.
DR SUPFAM; SSF143021; SSF143021; 1.
DR SUPFAM; SSF47060; SSF47060; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing;
KW Eukaryotic host gene expression shutoff by virus; Host cytoplasm;
KW Host gene expression shutoff by virus; Host mRNA suppression by virus;
KW Host nucleus; 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 PKR by virus;
KW Inhibition of host pre-mRNA processing by virus;
KW Inhibition of host RIG-I by virus; Inhibition of host RLR pathway by virus;
KW Interferon antiviral system evasion; Isopeptide bond; Reference proteome;
KW RNA-binding; Ubl conjugation; Viral immunoevasion.
FT CHAIN 1..230
FT /note="Non-structural protein 1"
FT /id="PRO_0000078945"
FT REGION 1..73
FT /note="RNA-binding and homodimerization"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04066"
FT REGION 180..215
FT /note="CPSF4-binding"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04066"
FT REGION 205..230
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 223..230
FT /note="PABPN1-binding"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04066"
FT MOTIF 34..38
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04066"
FT MOTIF 137..146
FT /note="Nuclear export signal"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04066"
FT CROSSLNK 20
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ISG15); in band I form; by host"
FT /evidence="ECO:0000269|PubMed:20385878"
FT CROSSLNK 41
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ISG15); in band I form; by host"
FT /evidence="ECO:0000269|PubMed:20385878"
FT CROSSLNK 108
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ISG15); in band II form; by host"
FT /evidence="ECO:0000269|PubMed:20385878"
FT CROSSLNK 110
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ISG15); in band II form; by host"
FT /evidence="ECO:0000269|PubMed:20385878"
FT CROSSLNK 126
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ISG15); in band II form; by host"
FT /evidence="ECO:0000269|PubMed:20385878"
FT CROSSLNK 217
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ISG15); in band I form; by host"
FT /evidence="ECO:0000269|PubMed:20385878"
FT CROSSLNK 219
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ISG15); in band I form; by host"
FT /evidence="ECO:0000269|PubMed:20385878"
FT MUTAGEN 20
FT /note="K->A: No of ISGylation of band I form; when
FT associated with K-41; K-217 and K-219."
FT /evidence="ECO:0000269|PubMed:20385878"
FT MUTAGEN 38
FT /note="R->A: Complete loss of inhibition of DDX58 CARD
FT ubiquitination; when associated with A-41."
FT /evidence="ECO:0000269|PubMed:19454348"
FT MUTAGEN 41
FT /note="K->A: Complete loss of inhibition of DDX58 CARD
FT ubiquitination; when associated with A-38."
FT /evidence="ECO:0000269|PubMed:19454348,
FT ECO:0000269|PubMed:20385878"
FT MUTAGEN 41
FT /note="K->A: No of ISGylation of band I form; when
FT associated with K-20; K-217 and K-219."
FT /evidence="ECO:0000269|PubMed:19454348,
FT ECO:0000269|PubMed:20385878"
FT MUTAGEN 96
FT /note="E->A: Complete loss of inhibition of DDX58 CARD
FT ubiquitination; when associated with A-97."
FT /evidence="ECO:0000269|PubMed:19454348"
FT MUTAGEN 97
FT /note="E->A: Complete loss of inhibition of DDX58 CARD
FT ubiquitination; when associated with A-96."
FT /evidence="ECO:0000269|PubMed:19454348"
FT MUTAGEN 108
FT /note="K->A: No of ISGylation of band II form; when
FT associated with K-110 and K-126."
FT /evidence="ECO:0000269|PubMed:20385878"
FT MUTAGEN 110
FT /note="K->A: No of ISGylation of band II form; when
FT associated with K-108 and K-126."
FT /evidence="ECO:0000269|PubMed:20385878"
FT MUTAGEN 126
FT /note="K->A: No of ISGylation of band II form; when
FT associated with K-108 and K-110."
FT /evidence="ECO:0000269|PubMed:20385878"
FT MUTAGEN 217
FT /note="K->A: No of ISGylation of band I form; when
FT associated with K-20; K-41 and K-219."
FT /evidence="ECO:0000269|PubMed:20385878"
FT MUTAGEN 219
FT /note="K->A: No of ISGylation of band I form; when
FT associated with K-20; K-41 and K-217."
FT /evidence="ECO:0000269|PubMed:20385878"
FT CONFLICT 55
FT /note="E -> K (in Ref. 4; ABD77680)"
FT CONFLICT 101
FT /note="D -> E (in Ref. 2; AAA43536)"
FT HELIX 3..24
FT /evidence="ECO:0007829|PDB:2ZKO"
FT HELIX 30..50
FT /evidence="ECO:0007829|PDB:2ZKO"
FT HELIX 54..69
FT /evidence="ECO:0007829|PDB:2ZKO"
FT STRAND 88..93
FT /evidence="ECO:0007829|PDB:3RVC"
FT HELIX 95..99
FT /evidence="ECO:0007829|PDB:3RVC"
FT STRAND 105..112
FT /evidence="ECO:0007829|PDB:3RVC"
FT STRAND 115..120
FT /evidence="ECO:0007829|PDB:3RVC"
FT STRAND 127..137
FT /evidence="ECO:0007829|PDB:3RVC"
FT STRAND 140..151
FT /evidence="ECO:0007829|PDB:3RVC"
FT STRAND 156..162
FT /evidence="ECO:0007829|PDB:3RVC"
FT HELIX 171..187
FT /evidence="ECO:0007829|PDB:3RVC"
FT STRAND 191..194
FT /evidence="ECO:0007829|PDB:3RVC"
FT HELIX 196..201
FT /evidence="ECO:0007829|PDB:3RVC"
SQ SEQUENCE 230 AA; 25868 MW; 2F7EC18E3EE7A4BE CRC64;
MDPNTVSSFQ VDCFLWHVRK RVADQELGDA PFLDRLRRDQ KSLRGRGSTL GLDIETATRA
GKQIVERILK EESDEALKMT MASVPASRYL TDMTLEEMSR DWSMLIPKQK VAGPLCIRMD
QAIMDKNIIL KANFSVIFDR LETLILLRAF TEEGAIVGEI SPLPSLPGHT AEDVKNAVGV
LIGGLEWNDN TVRVSETLQR FAWRSSNENG RPPLTPKQKR EMAGTIRSEV
