ID   NS1_I18A0               Reviewed;         230 AA.
AC   Q99AU3;
DT   13-NOV-2007, integrated into UniProtKB/Swiss-Prot.
DT   01-JUN-2001, sequence version 1.
DT   08-NOV-2023, entry version 98.
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/Brevig Mission/1/1918 H1N1) (Influenza A virus
OS   (strain A/South Carolina/1/1918 H1N1)).
OC   Viruses; Riboviria; Orthornavirae; Negarnaviricota; Polyploviricotina;
OC   Insthoviricetes; Articulavirales; Orthomyxoviridae; Alphainfluenzavirus;
OC   Alphainfluenzavirus influenzae; Influenza A virus.
OX   NCBI_TaxID=88776;
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=11226311; DOI=10.1073/pnas.031575198;
RA   Basler C.F., Reid A.H., Dybing J.K., Janczewski T.A., Fanning T.G.,
RA   Zheng H., Salvatore M., Perdue M.L., Swayne D.E., Garcia-Sastre A.,
RA   Palese P., Taubenberger J.K.;
RT   "Sequence of the 1918 pandemic influenza virus nonstructural gene (NS)
RT   segment and characterization of recombinant viruses bearing the 1918 NS
RT   genes.";
RL   Proc. Natl. Acad. Sci. U.S.A. 98:2746-2751(2001).
RN   [2]
RP   INTERACTION WITH HUMAN TRIM25.
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).
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. Prevents the establishment of the cellular antiviral state
CC       by inhibiting TRIM25-mediated RIGI 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. Also binds
CC       poly(A) and U6 snRNA. Inhibits the integrated stress response (ISR) in
CC       the infected cell by blocking dsRNA binding by EIF2AK2/PKR and further
CC       phosphorylation of EIF2S1/EIF-2ALPHA. Stress granule formation is thus
CC       inhibited, which allows protein synthesis and viral replication.
CC       {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 RIGI CARD ubiquitination. Interacts with human EIF2AK2/PKR,
CC       CPSF4, IVNS1ABP and PABPN1. {ECO:0000255|HAMAP-Rule:MF_04066}.
CC   -!- INTERACTION:
CC       Q99AU3; O95786-1: RIGI; Xeno; NbExp=2; IntAct=EBI-6150155, EBI-15577823;
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=Q99AU3-1; Sequence=Displayed;
CC       Name=NEP; Synonyms=NS2;
CC         IsoId=Q77IX1-1; 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       {ECO:0000255|HAMAP-Rule:MF_04066}.
CC   -!- MISCELLANEOUS: South Carolina isolate has been sequenced from formalid
CC       fixed-lung tissues of a 21-year-old male which died in 1918 at Ft.
CC       Jackson, SC. Brevig Mission isolate has been sequenced from lung
CC       tissues of an Inuit woman buried in the permafrost in a gravesite near
CC       Brevig Mission, Alaska. This sample was recovered by John Hultin,
CC       retired pathologist.
CC   -!- SIMILARITY: Belongs to the influenza A viruses NS1 family.
CC       {ECO:0000255|HAMAP-Rule:MF_04066}.
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DR   EMBL; AF333238; AAK14368.1; -; Genomic_RNA.
DR   PDB; 2N74; NMR; -; A/B=1-73.
DR   PDB; 5UL6; X-ray; 1.45 A; M=210-221.
DR   PDB; 6ATV; X-ray; 1.75 A; M=210-221.
DR   PDB; 6DGK; X-ray; 1.90 A; A/B=86-205.
DR   PDB; 6NU0; NMR; -; A=1-230.
DR   PDB; 6OX7; X-ray; 2.75 A; A/B=86-230.
DR   PDB; 6U28; X-ray; 2.95 A; A/B=86-230.
DR   PDBsum; 2N74; -.
DR   PDBsum; 5UL6; -.
DR   PDBsum; 6ATV; -.
DR   PDBsum; 6DGK; -.
DR   PDBsum; 6NU0; -.
DR   PDBsum; 6OX7; -.
DR   PDBsum; 6U28; -.
DR   BMRB; Q99AU3; -.
DR   SMR; Q99AU3; -.
DR   DIP; DIP-61813N; -.
DR   IntAct; Q99AU3; 24.
DR   Proteomes; UP000008430; 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: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; Influenza virus non-structural protein, effector domain; 1.
DR   Gene3D; 1.10.287.10; S15/NS1, RNA-binding; 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; uS15_NS1_RNA-bd_sf.
DR   Pfam; PF00600; Flu_NS1; 1.
DR   SUPFAM; SSF143021; Ns1 effector domain-like; 1.
DR   SUPFAM; SSF47060; S15/NS1 RNA-binding domain; 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; RNA-binding; Ubl conjugation;
KW   Viral immunoevasion.
FT   CHAIN           1..230
FT                   /note="Non-structural protein 1"
FT                   /id="PRO_0000310570"
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   HELIX           4..23
FT                   /evidence="ECO:0007829|PDB:2N74"
FT   TURN            24..26
FT                   /evidence="ECO:0007829|PDB:2N74"
FT   HELIX           31..50
FT                   /evidence="ECO:0007829|PDB:2N74"
FT   HELIX           54..71
FT                   /evidence="ECO:0007829|PDB:2N74"
FT   STRAND          88..93
FT                   /evidence="ECO:0007829|PDB:6DGK"
FT   HELIX           95..99
FT                   /evidence="ECO:0007829|PDB:6DGK"
FT   STRAND          105..112
FT                   /evidence="ECO:0007829|PDB:6DGK"
FT   STRAND          115..120
FT                   /evidence="ECO:0007829|PDB:6DGK"
FT   STRAND          127..137
FT                   /evidence="ECO:0007829|PDB:6DGK"
FT   STRAND          140..151
FT                   /evidence="ECO:0007829|PDB:6DGK"
FT   STRAND          156..162
FT                   /evidence="ECO:0007829|PDB:6DGK"
FT   HELIX           171..187
FT                   /evidence="ECO:0007829|PDB:6DGK"
FT   STRAND          191..194
FT                   /evidence="ECO:0007829|PDB:6DGK"
FT   HELIX           196..203
FT                   /evidence="ECO:0007829|PDB:6DGK"
SQ   SEQUENCE   230 AA;  26066 MW;  B3257EA296ADA840 CRC64;
     MDSNTVSSFQ VDCFLWHVRK RFADQELGDA PFLDRLRRDQ KSLRGRGSTL GLDIETATRA
     GKQIVERILK EESDEALKMT IASVPASRYL TDMTLEEMSR DWFMLMPKQK VAGSLCIRMD
     QAIMDKNIIL KANFSVIFDR LETLILLRAF TEEGAIVGEI SPLPSLPGHT DEDVKNAVGV
     LIGGLEWNDN TVRVSETLQR FAWRSSNENG RPPLPPKQKR KMARTIKSEV
//