NSS_SFTSV
ID NSS_SFTSV Reviewed; 293 AA.
AC A0A0B5AC19; F1BA49;
DT 03-AUG-2022, integrated into UniProtKB/Swiss-Prot.
DT 01-APR-2015, sequence version 1.
DT 03-AUG-2022, entry version 14.
DE RecName: Full=Non-structural protein NS-S;
DE Short=NSs;
GN Name=NSS;
OS SFTS phlebovirus (isolate SFTSV/Human/China/HB29/2010) (Severe fever with
OS thrombocytopenia virus).
OC Viruses; Riboviria; Orthornavirae; Negarnaviricota; Polyploviricotina;
OC Ellioviricetes; Bunyavirales; Phenuiviridae; Bandavirus; Dabie bandavirus.
OX NCBI_TaxID=992212;
OH NCBI_TaxID=44386; Haemaphysalis longicornis (Bush tick).
OH NCBI_TaxID=9606; Homo sapiens (Human).
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=21410387; DOI=10.1056/nejmoa1010095;
RA Yu X.J., Liang M.F., Zhang S.Y., Liu Y., Li J.D., Sun Y.L., Zhang L.,
RA Zhang Q.F., Popov V.L., Li C., Qu J., Li Q., Zhang Y.P., Hai R., Wu W.,
RA Wang Q., Zhan F.X., Wang X.J., Kan B., Wang S.W., Wan K.L., Jing H.Q.,
RA Lu J.X., Yin W.W., Zhou H., Guan X.H., Liu J.F., Bi Z.Q., Liu G.H., Ren J.,
RA Wang H., Zhao Z., Song J.D., He J.R., Wan T., Zhang J.S., Fu X.P.,
RA Sun L.N., Dong X.P., Feng Z.J., Yang W.Z., Hong T., Zhang Y., Walker D.H.,
RA Wang Y., Li D.X.;
RT "Fever with thrombocytopenia associated with a novel bunyavirus in China.";
RL N. Engl. J. Med. 364:1523-1532(2011).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=HB29;
RX PubMed=25552716; DOI=10.1128/jvi.03432-14;
RA Brennan B., Li P., Zhang S., Li A., Liang M., Li D., Elliott R.M.;
RT "A reverse genetic system for severe fever with thrombocytopenia syndrome
RT virus.";
RL J. Virol. 89:3026-3037(2015).
RN [3]
RP FUNCTION, INTERACTION WITH HOST TRIM25, INTERACTION WITH HOST DDX58,
RP INTERACTION WITH HOST TBK1, AND SUBCELLULAR LOCATION.
RX PubMed=24478431; DOI=10.1128/jvi.03021-13;
RA Santiago F.W., Covaleda L.M., Sanchez-Aparicio M.T., Silvas J.A.,
RA Diaz-Vizarreta A.C., Patel J.R., Popov V., Yu X.J., Garcia-Sastre A.,
RA Aguilar P.V.;
RT "Hijacking of RIG-I signaling proteins into virus-induced cytoplasmic
RT structures correlates with the inhibition of type I interferon responses.";
RL J. Virol. 88:4572-4585(2014).
RN [4]
RP FUNCTION, MUTAGENESIS OF 66-PRO--PRO-69, AND INTERACTION WITH HOST TBK1.
RX PubMed=24706939; DOI=10.1093/jmcb/mju015;
RA Ning Y.J., Wang M., Deng M., Shen S., Liu W., Cao W.C., Deng F., Wang Y.Y.,
RA Hu Z., Wang H.;
RT "Viral suppression of innate immunity via spatial isolation of
RT TBK1/IKKepsilon from mitochondrial antiviral platform.";
RL J. Mol. Cell Biol. 6:324-337(2014).
RN [5]
RP FUNCTION, INTERACTION WITH HOST TBK1, AND SUBCELLULAR LOCATION.
RX PubMed=24335286; DOI=10.1128/jvi.03510-13;
RA Wu X., Qi X., Qu B., Zhang Z., Liang M., Li C., Cardona C.J., Li D.,
RA Xing Z.;
RT "Evasion of antiviral immunity through sequestering of TBK1/IKKepsilon/IRF3
RT into viral inclusion bodies.";
RL J. Virol. 88:3067-3076(2014).
RN [6]
RP FUNCTION, AND INTERACTION WITH HOST STAT2.
RX PubMed=25631085; DOI=10.1128/jvi.00154-15;
RA Ning Y.J., Feng K., Min Y.Q., Cao W.C., Wang M., Deng F., Hu Z., Wang H.;
RT "Disruption of type I interferon signaling by the nonstructural protein of
RT severe fever with thrombocytopenia syndrome virus via the hijacking of
RT STAT2 and STAT1 into inclusion bodies.";
RL J. Virol. 89:4227-4236(2015).
RN [7]
RP INTERACTION WITH HOST SYNGR2, SUBCELLULAR LOCATION, AND FUNCTION.
RX PubMed=27226560; DOI=10.1074/jbc.m116.715599;
RA Sun Q., Qi X., Zhang Y., Wu X., Liang M., Li C., Li D., Cardona C.J.,
RA Xing Z.;
RT "Synaptogyrin-2 promotes replication of a novel tick-borne bunyavirus
RT through interacting with viral nonstructural protein NSs.";
RL J. Biol. Chem. 291:16138-16149(2016).
RN [8]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=28680969; DOI=10.1128/msphere.00234-17;
RA Rezelj V.V., Li P., Chaudhary V., Elliott R.M., Jin D.Y., Brennan B.;
RT "Differential Antagonism of Human Innate Immune Responses by Tick-Borne
RT Phlebovirus Nonstructural Proteins.";
RL MSphere 2:0-0(2017).
RN [9]
RP FUNCTION, MUTAGENESIS OF 66-PRO--PRO-69, AND INTERACTION WITH HOST STAT2.
RX PubMed=29886262; DOI=10.1016/j.micinf.2018.05.007;
RA Kitagawa Y., Sakai M., Shimojima M., Saijo M., Itoh M., Gotoh B.;
RT "Nonstructural protein of severe fever with thrombocytopenia syndrome
RT phlebovirus targets STAT2 and not STAT1 to inhibit type I interferon-
RT stimulated JAK-STAT signaling.";
RL Microbes Infect. 20:360-368(2018).
RN [10]
RP FUNCTION, INTERACTION WITH HOST TBK1, AND MUTAGENESIS OF 21-VAL--LEU-23;
RP 24-VAL--LEU-26; 27-VAL--LEU-29 AND 66-PRO--PRO-69.
RX PubMed=30021900; DOI=10.1128/jvi.00706-18;
RA Moriyama M., Igarashi M., Koshiba T., Irie T., Takada A., Ichinohe T.;
RT "Two Conserved Amino Acids within the NSs of Severe Fever with
RT Thrombocytopenia Syndrome Phlebovirus Are Essential for Anti-interferon
RT Activity.";
RL J. Virol. 92:0-0(2018).
RN [11]
RP FUNCTION, INTERACTION WITH HOST IRF7, AND SUBCELLULAR LOCATION.
RX PubMed=30598516; DOI=10.4049/jimmunol.1800576;
RA Hong Y., Bai M., Qi X., Li C., Liang M., Li D., Cardona C.J., Xing Z.;
RT "Suppression of the IFN-alpha and -beta Induction through Sequestering IRF7
RT into Viral Inclusion Bodies by Nonstructural Protein NSs in Severe Fever
RT with Thrombocytopenia Syndrome Bunyavirus Infection.";
RL J. Immunol. 202:841-856(2019).
RN [12]
RP FUNCTION, INTERACTION WITH HOST TNIP2, AND MUTAGENESIS OF 66-PRO--PRO-69;
RP PRO-102; 133-TRP--LEU-136 AND LYS-211.
RX PubMed=30617349; DOI=10.1038/s41564-018-0329-x;
RA Choi Y., Park S.J., Sun Y., Yoo J.S., Pudupakam R.S., Foo S.S., Shin W.J.,
RA Chen S.B., Tsichlis P.N., Lee W.J., Lee J.S., Li W., Brennan B., Choi Y.K.,
RA Jung J.U.;
RT "Severe fever with thrombocytopenia syndrome phlebovirus non-structural
RT protein activates TPL2 signalling pathway for viral immunopathogenesis.";
RL Nat. Microbiol. 4:429-437(2019).
RN [13]
RP INTERACTION WITH HOST STAT2.
RX PubMed=30814285; DOI=10.1128/jvi.02226-18;
RA Yoshikawa R., Sakabe S., Urata S., Yasuda J.;
RT "Species-Specific Pathogenicity of Severe Fever with Thrombocytopenia
RT Syndrome Virus Is Determined by Anti-STAT2 Activity of NSs.";
RL J. Virol. 93:0-0(2019).
RN [14]
RP INTERACTION WITH HOST TRIM21, AND MUTAGENESIS OF 226-LYS--GLY-230.
RX PubMed=31852783; DOI=10.1128/jvi.01684-19;
RA Choi Y., Jiang Z., Shin W.J., Jung J.U.;
RT "Severe Fever with Thrombocytopenia Syndrome Virus NSs Interacts with
RT TRIM21 To Activate the p62-Keap1-Nrf2 Pathway.";
RL J. Virol. 94:0-0(2020).
RN [15]
RP FUNCTION, AND INTERACTION WITH HOST CDK1.
RX PubMed=31852787; DOI=10.1128/jvi.01575-19;
RA Liu S., Liu H., Kang J., Xu L., Zhang K., Li X., Hou W., Wang Z., Wang T.;
RT "The Severe Fever with Thrombocytopenia Syndrome Virus NSs Protein
RT Interacts with CDK1 To Induce G2 Cell Cycle Arrest and Positively Regulate
RT Viral Replication.";
RL J. Virol. 94:0-0(2020).
RN [16]
RP FUNCTION.
RX PubMed=33288641; DOI=10.1128/mcb.00542-20;
RA Khalil J., Yamada S., Tsukamoto Y., Abe H., Shimojima M., Kato H.,
RA Fujita T.;
RT "The Non-structural Protein NSs of SFTSV Causes Cytokine Storm Through the
RT Hyper-activation of NF-kappaB.";
RL Mol. Cell. Biol. 0:0-0(2020).
RN [17]
RP INTERACTION WITH HOST TRIM25, INTERACTION WITH HOST TBK1, AND FUNCTION.
RX PubMed=32471869; DOI=10.1074/jbc.ra120.013973;
RA Min Y.Q., Ning Y.J., Wang H., Deng F.;
RT "A RIG-I-like receptor directs antiviral responses to a bunyavirus and is
RT antagonized by virus-induced blockade of TRIM25-mediated ubiquitination.";
RL J. Biol. Chem. 295:9691-9711(2020).
CC -!- FUNCTION: Sequesters host STAT2 into viral inclusion bodies (Probable)
CC (PubMed:29886262). Impairs IFN-stimulated phosphorylation and nuclear
CC translocation of host STAT2, thereby suppressing type-I IFN antiviral
CC signaling (Probable) (PubMed:29886262, PubMed:28680969). Sequesters
CC host TRIM25, DDX58/RIG-I, TBK1/IKK complex components (TBK1,
CC IKBKE/IKKE, and IRF3) and IRF7 into viral inclusion bodies, thereby
CC inhibiting the IFN responses (Probable). Inhibits TRIM25-mediated
CC ubiquitination of the DDX58/RIG-I (PubMed:32471869). The sequestration
CC of IKBKE/IKKE, and IRF3 occurs via the interaction with TBK1
CC (PubMed:24335286). Sequestration and inhibition of host TBK1 probably
CC participates to the cytokine storm induced by the virus
CC (PubMed:33288641). Also inhibits the phosphorylation of host TBK1
CC (PubMed:28680969). Interacts with host TNIP2 and promotes TPL2-TNIP2-
CC p105 complex formation leading to IL-10 induction (PubMed:30617349). By
CC interacting with CDK1, induces host cell arrest at the G2/M transition
CC to promote viral replication (PubMed:31852787). Requested for the
CC formation of the viral cytoplasmic inclusion bodies (PubMed:24335286,
CC PubMed:27226560). {ECO:0000269|PubMed:24335286,
CC ECO:0000269|PubMed:27226560, ECO:0000269|PubMed:28680969,
CC ECO:0000269|PubMed:29886262, ECO:0000269|PubMed:30617349,
CC ECO:0000269|PubMed:31852787, ECO:0000269|PubMed:32471869,
CC ECO:0000269|PubMed:33288641, ECO:0000305|PubMed:24478431,
CC ECO:0000305|PubMed:24706939, ECO:0000305|PubMed:25631085,
CC ECO:0000305|PubMed:30021900, ECO:0000305|PubMed:30598516}.
CC -!- SUBUNIT: Interacts with the host E3 ubiquitin ligase TRIM25; this
CC interaction sequesters TRIM25 in NSs-induced cytoplasmic inclusion
CC bodies (PubMed:24478431, PubMed:32471869). Interacts with the host E3
CC ubiquitin ligase DDX58/RIG-I; this interaction sequesters DDX58/RIG-I
CC in NSs-induced cytoplasmic inclusion bodies (PubMed:24478431).
CC Interacts with the host E3 ubiquitin ligase TBK1 (via N-terminus); this
CC interaction sequesters TBK1 in NSs-induced cytoplasmic inclusion bodies
CC and inhibits TBK1 phosphorylation (PubMed:24478431, PubMed:24706939,
CC PubMed:24335286, PubMed:30021900, PubMed:32471869). NSs does not
CC interact with IKBKE/IKKE or IRF3 (PubMed:24335286). Interacts with host
CC IRF7; this interaction sequesters IRF7 in NSs-induced cytoplasmic
CC inclusion bodies (PubMed:30598516). Interacts with host SYNGR2; this
CC interaction is essential to promoting the formation of the inclusion
CC bodies to become virus factories for viral RNA replication through its
CC interaction with NSs (PubMed:27226560). Interacts with host STAT2; this
CC interaction sequesters STAT2 in NSs-induced cytoplasmic inclusion
CC bodies (PubMed:29886262, PubMed:25631085) (Probable). Interacts with
CC host TNIP2; this interaction promotes TPL2 complex formation and
CC signaling activity leading to IL-10 production (PubMed:30617349).
CC Interacts with host TRIM21 (via B30.2/SPRY domain); this interaction
CC activates host NFE2L2-mediated transcriptional activation of
CC antioxidant genes (PubMed:31852783). Interacts with host CDK1; this
CC interaction is inclusion body dependent, it inhibits the formation and
CC nuclear import of the cyclin B1-CDK1 complex and leads to host cell
CC cycle arrest (PubMed:31852787). {ECO:0000269|PubMed:24335286,
CC ECO:0000269|PubMed:24478431, ECO:0000269|PubMed:24706939,
CC ECO:0000269|PubMed:25631085, ECO:0000269|PubMed:27226560,
CC ECO:0000269|PubMed:29886262, ECO:0000269|PubMed:30021900,
CC ECO:0000269|PubMed:30598516, ECO:0000269|PubMed:30617349,
CC ECO:0000269|PubMed:31852783, ECO:0000269|PubMed:31852787,
CC ECO:0000269|PubMed:32471869, ECO:0000305|PubMed:30814285}.
CC -!- SUBCELLULAR LOCATION: Host cytoplasm {ECO:0000269|PubMed:24478431}.
CC Host cytoplasmic vesicle {ECO:0000269|PubMed:24335286,
CC ECO:0000269|PubMed:28680969, ECO:0000269|PubMed:30598516}.
CC Note=Localizes to the viral cytoplasmic occlusion bodies.
CC {ECO:0000269|PubMed:24335286, ECO:0000269|PubMed:27226560,
CC ECO:0000269|PubMed:28680969, ECO:0000269|PubMed:30598516}.
CC -!- SIMILARITY: Belongs to the Bandavirus NS-S protein family.
CC {ECO:0000305}.
CC -!- CAUTION: PubMed:32471869 did not detect any interaction between NSs and
CC host DDX58/RIG-I, nor NSs-induced sequestration of DDX58/RIG-I in
CC cytoplasmic inclusion bodies. {ECO:0000305}.
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DR EMBL; HM745932; ADZ04473.1; -; Genomic_RNA.
DR EMBL; KP202165; AJD86041.1; -; Genomic_RNA.
DR RefSeq; YP_006504093.1; NC_018137.1.
DR IntAct; F1BA49; 4.
DR GeneID; 13231113; -.
DR KEGG; vg:13231113; -.
DR Proteomes; UP000117954; Genome.
DR Proteomes; UP000201130; Genome.
DR InterPro; IPR039434; NSs-like.
DR Pfam; PF11073; NSs; 1.
PE 1: Evidence at protein level;
KW Host cytoplasm; Host cytoplasmic vesicle;
KW Host G2/M cell cycle arrest by virus; 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 RIG-I by virus; Inhibition of host RLR pathway by virus;
KW Inhibition of host STAT2 by virus; Inhibition of host TBK1 by virus;
KW Inhibition of host TLR pathway by virus;
KW Modulation of host cell cycle by virus; Reference proteome;
KW Viral immunoevasion.
FT CHAIN 1..293
FT /note="Non-structural protein NS-S"
FT /id="PRO_0000456169"
FT REGION 21..29
FT /note="Essential for inhibition of IFN-beta activation and
FT interaction with host TBK1"
FT /evidence="ECO:0000269|PubMed:30021900"
FT REGION 66..69
FT /note="Involved in inclusion bodies formation"
FT /evidence="ECO:0000269|PubMed:24706939,
FT ECO:0000269|PubMed:30021900"
FT REGION 148..220
FT /note="Interaction with host TNIP2"
FT /evidence="ECO:0000269|PubMed:30617349"
FT SITE 21
FT /note="Essential for suppression of TBK1/IRF3-mediated IFN
FT response"
FT /evidence="ECO:0000269|PubMed:30021900"
FT SITE 23
FT /note="Essential for suppression of TBK1/IRF3-mediated IFN
FT response"
FT /evidence="ECO:0000269|PubMed:30021900"
FT MUTAGEN 21..23
FT /note="VRL->ARA: Almost complete loss of the inhibition of
FT IFN-beta activation and interaction with host TBK1."
FT /evidence="ECO:0000269|PubMed:30021900"
FT MUTAGEN 24..26
FT /note="EPS->APA: Almost complete loss of the inhibition of
FT IFN-beta activation and interaction with host TBK1."
FT /evidence="ECO:0000269|PubMed:30021900"
FT MUTAGEN 27..29
FT /note="LGE->AGA: 50% loss of the inhibition of IFN-beta
FT promoter activity and loss of interaction with host TBK1."
FT /evidence="ECO:0000269|PubMed:30021900"
FT MUTAGEN 66..69
FT /note="PKNP->AKNA: Disruption of NSs-induced inclusion
FT bodies and loss of inhibition of the host IFN responses. No
FT effect on the interaction with host STAT2; complete loss of
FT inhibition of IFN-stimulated phosphorylation of STAT2."
FT /evidence="ECO:0000269|PubMed:24706939,
FT ECO:0000269|PubMed:29886262"
FT MUTAGEN 66..69
FT /note="PKNP->AKNA: Loss of ability to sequester host TBK1
FT into viral cytoplasmic vesicles."
FT /evidence="ECO:0000269|PubMed:30021900,
FT ECO:0000269|PubMed:30617349"
FT MUTAGEN 102
FT /note="P->A: Complete loss of ability to induce TPL2
FT signaling and IL-10 production and drastically reduced
FT pathogenesis. Complete loss of formation of NSs-induced
FT inclusion bodies and secretion of IFN-beta. Stronger
FT interaction with host ABIN2."
FT /evidence="ECO:0000269|PubMed:30617349"
FT MUTAGEN 133..136
FT /note="WRGL->ARGA: No effect on the formation of NSs-
FT induced inclusion bodies."
FT /evidence="ECO:0000269|PubMed:30617349"
FT MUTAGEN 211
FT /note="K->R: Complete loss of interaction with host ABIN2
FT and ability to induce host TPL2 signaling and IL-10
FT production. Drastically reduced pathogenesis. No effect on
FT the formation of NSs-induced inclusion bodies and secretion
FT of IFN-beta."
FT /evidence="ECO:0000269|PubMed:30617349"
FT MUTAGEN 226..230
FT /note="KKTDG->AAAAA: Complete loss of interaction with host
FT TRIM21 and NFE2L2-mediated transcriptional activation. No
FT effet on the formation of NSs-induced inclusion bodies.
FT Delay in pathogenesis."
FT /evidence="ECO:0000269|PubMed:31852783"
FT MUTAGEN 282..284
FT /note="DWP->AAA: No effect on the formation of NSs-induced
FT inclusion bodies."
FT /evidence="ECO:0000269|PubMed:30617349"
FT CONFLICT 197
FT /note="M -> L (in Ref. 1; ADZ04473)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 293 AA; 33793 MW; CEF54E3E18CBA677 CRC64;
MSLSKCSNVD LKSVAMNANT VRLEPSLGEY PTLRRDLVEC SCSVLTLSMV KRMGKMTNTV
WLFGNPKNPL HQLEPGLEQL LDMYYKDMRC YSQRELSALR WPSGKPSVWF LQAAHMFFSI
KNSWAMETGR ENWRGLFHRI TKGQKYLFEG DMILDSLEAI EKRRLRLGLP EILITGLSPI
LDVALLQIES LARLRGMSLN HHLFTSPSLR KPLLDCWDFF IPVRKKKTDG SYSVLDEDDE
PGVLHGYPHL MAHYLNRCPF HNLIRFDEEL RTAALNTIWG RDWPAIGDLP KEV
