ID   NS1_I47A0               Reviewed;         202 AA.
AC   P03499; Q77AL3;
DT   21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT   21-JUL-1986, sequence version 1.
DT   08-NOV-2023, entry version 103.
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/Fort Monmouth/1/1947 H1N1).
OC   Viruses; Riboviria; Orthornavirae; Negarnaviricota; Polyploviricotina;
OC   Insthoviricetes; Articulavirales; Orthomyxoviridae; Alphainfluenzavirus;
OC   Alphainfluenzavirus influenzae; Influenza A virus.
OX   NCBI_TaxID=380282;
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=6834468; DOI=10.1128/jvi.45.2.547-554.1983;
RA   Krystal M., Buonagurio D.A., Young J.F., Palese P.;
RT   "Sequential mutations in the NS genes of influenza virus field strains.";
RL   J. Virol. 45:547-554(1983).
RN   [2]
RP   NUCLEOTIDE SEQUENCE.
RC   STRAIN=A/FM/1/47-MA;
RX   PubMed=8254767; DOI=10.1128/jvi.68.1.530-534.1994;
RA   Smeenk C.A., Brown E.G.;
RT   "The influenza virus variant A/FM/1/47-MA possesses single amino acid
RT   replacements in the hemagglutinin, controlling virulence, and in the matrix
RT   protein, controlling virulence as well as growth.";
RL   J. Virol. 68:530-534(1994).
RN   [3]
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).
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   -!- 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=P03499-1; Sequence=Displayed;
CC       Name=NEP; Synonyms=NS2;
CC         IsoId=P03506-1; 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   -!- SIMILARITY: Belongs to the influenza A viruses NS1 family.
CC       {ECO:0000255|HAMAP-Rule:MF_04066}.
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DR   EMBL; K00577; AAA43522.1; -; Genomic_RNA.
DR   EMBL; AJ238022; CAB50889.1; -; Genomic_RNA.
DR   SMR; P03499; -.
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   3: Inferred from homology;
KW   Alternative splicing; Eukaryotic host gene expression shutoff by virus;
KW   Host cytoplasm; Host gene expression shutoff by virus;
KW   Host mRNA suppression by virus; 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..202
FT                   /note="Non-structural protein 1"
FT                   /id="PRO_0000078928"
FT   REGION          1..73
FT                   /note="RNA-binding and homodimerization"
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   VARIANT         139
FT                   /note="G -> D (in strain: A/FM/1/47-MA)"
SQ   SEQUENCE   202 AA;  22680 MW;  F3663BCC89E68978 CRC64;
     MDPNTVSSFQ VDCFLWHVRK RVADQELGDA PFLDRLRRDQ KSLKGRGSTL GLNIETATRV
     GKQIVERILK EESDEALKMT MASAPASRYL TDMTIEEMSR DWFMLMPKQK VAGPLCIRMD
     QAIMDKSIIL KANFSVIFGR LETLILLRAF TEEGAIVGEI SPLPSLPGHT NEDVKNAIGV
     LIGGLEWNDN TVRVSKTLQR FA
//