ライフサイエンスコーパス: NS5

1 NS5 has 5'-RNA methyltransferase (MT)/guanylyltransferas

2 NS5 was found to be monomeric and well-folded under the

3 ver, previous studies have shown that DENV-2 NS5 accumulates in the nucleus during infection.

4 V-2 NS5, did not substantially affect DENV-2 NS5 nuclear localization, whereas knockdown of importin-

5 a isoform previously shown to bind to DENV-2 NS5, did not substantially affect DENV-2 NS5 nuclear loc

6 te the structure and dynamics of DENV type 3 NS5 in solution, we conducted small-angle X-ray scatteri

7 Interaction studies using DENV-2 and -4 NS5 and human importin-alpha isoforms failed to identify

8 ins accumulate in the nucleus, DENV-1 and -4 NS5 are predominantly if not exclusively localized to th

9 Comparative studies on the DENV-2 and -4 NS5 proteins revealed that the difference in DENV-4 NS5

10 teins revealed that the difference in DENV-4 NS5 nuclear localization was not due to rapid nuclear ex

11 he large flavivirus nonstructural protein 5 (NS5) (105 kDa) has RNA methyltransferase activities at i

12 probes, located at nonstructural protein 5 (NS5) and the 3' noncoding region (3'NC) of DENV.

13 engue virus (DENV) non-structural protein 5 (NS5) comprises an N-terminal methyltransferase and a C-t

14 Nonstructural protein 5 (NS5) contains a methyltransferase for RNA capping and a

15 DENV non-structural protein 5 (NS5) contains enzymatic activities required for capping

16 We report that nonstructural protein 5 (NS5) from four serocomplexes of flaviviruses specificall

17 sphorylation of the nonstructural protein 5 (NS5) is a conserved feature of flaviviruses, but the kin

18 Dengue virus (DENV) nonstructural protein 5 (NS5) is composed of two globular domains separated by a

19 irst time, that the nonstructural protein 5 (NS5) mediates both guanine N-7 and ribose 2'-O methylati

20 n complex with the non-structural protein 5 (NS5) of Zika virus (ZIKV) and dengue virus (DENV), revea

21 construct expressed nonstructural protein 5 (NS5), while a second recombinant expressed a soluble var

22 sitions P4-P2' surrounding the NS2-3, NS4-5, NS5-6, and NS6-7 cleavage sites contain all of the struc

23 eaved rapidly and three "late" sites (NS4-5, NS5-6, and NS6-7) processed subsequently and less effici

24 helicase and covalently linked NS3(172-618)-NS5(320-341) reveals a rigid and compact formation of th

25 Cellular immune responses against NS5 were also elicited, as evidenced by major histocompa

26 All NS5 cDNA sequences are encoded by three loci, of which t

27 All NS5 proteins inhibited HIV replication.

28 CD8 T-cell lines specific for NS3-1073 and NS5-2594 were expanded from HCV-seropositive persons by

29 observed with the addition of the NS1/2A and NS5 vaccine virus genome regions.

30 HCV proteins core, nonstructural (NS) 3, and NS5.

31 HCV antigens (core, nonstructural NS3/4 and NS5) and control phytohemagglutinin (PHA) was monitored

32 stering was similarly broad in the E1/E2 and NS5 regions.

33 unctional proteins NS3 protease/helicase and NS5 methyltransferase/RNA-dependent RNA polymerase form

34 by nonstructural protein 3 (NS3), NS2A, and NS5 were the most targeted proteins.

35 NS3 recruits NS2B and NS5 proteins to form complexes possessing protease and r

36 ntly on the capsid and nonstructural NS3 and NS5 antigens.

37 NS3 and NS5 are highly conserved among the four serotypes, and t

38 Those within NS3 and NS5 are located at the surface and/or within the NS5 dim

39 Flavivirus NS3 and NS5 are required in viral replication and 5'-capping.

40 erotype-specific interaction between NS3 and NS5 as well as specific interdomain interaction within N

41 se in IL-10 secretion in response to NS3 and NS5 in subjects with HCV compared with HIV and HCV coinf

42 the pinpointed amino acids from the NS3 and NS5 regions are also conserved.

43 ncestry with the Flaviviridae in the NS3 and NS5 regions.

44 s to nonstructural proteins 3 and 5 (NS3 and NS5).

45 core protein, nonstructural proteins NS3 and NS5, and recall antigens tetanus toxoid and Candida.

46 In DEN2-infected mammalian cells, NS3 and NS5, the viral 5'-RNA methyltransferase/polymerase, exis

47 is required for interaction between NS3 and NS5.

48 hly conserved nonstructural proteins NS3 and NS5.

49 n each of the nonstructural proteins NS3 and NS5.

50 )- alpha against HCV proteins Core, NS3, and NS5 and recall antigens.

51 ls targeting the nonstructural NS1, NS3, and NS5 proteins of TDV-2.

52 and the remaining 86, chiefly of E, NS3, and NS5, shared an identity of nine or more consecutive amin

53 s localized to antigens E1, E2, p7, NS3, and NS5.

54 -IgG reactivities to the core, NS3, NS4, and NS5 HCV recombinant proteins and applied it to 99 serum

55 s from the viral core, E1, E2, NS3, NS4, and NS5 regions and different subtype-specific regions of th

56 ns: the core, E1, E2/NS1, NS2, NS3, NS4, and NS5 regions.

57 ype specific for E2, E2-HVR-1, NS3, NS4, and NS5 were detected in a minority of serum samples.

58 he nonstructural (NS) proteins NS3, NS4, and NS5, each of which was detected by >30% of subjects, but

59 he HCV non-structural antigens NS3, NS4, and NS5, were previously reported to induce robust and susta

60 , E2 HVR1-plus-HVR2 consensus, NS3, NS4, and NS5.

61 d among the HCV proteins core, NS3, NS4, and NS5.

62 ence of antibody reactivity to NS3, NS4, and NS5.

63 in regions encoding the NS1, NS2A, NS4A, and NS5 proteins and in the 3' untranslated region (UTR).

64 ences in the nonstructural proteins NS4b and NS5, a presumed transport protein and the viral RNA poly

65 hin the immunogenic regions of NS3, NS4B and NS5.

66 fferences were seen in the prM, E, NS4b, and NS5 genes, while sequence differences observed within th

67 rent viral proteins (E, NS2b, NS3, NS4b, and NS5) were discovered as unique to HLA-A*0201 of infected

68 inst the HCV c-22(p), c-33(p), c-100(p), and NS5 proteins, individually or combined, but it increased

69 tantly, inhibition of JAK-STAT signaling and NS5-IFN receptor interactions were demonstrated in LGTV-

70 Additionally, the K252 SUMOylation site and NS5 nuclear localization were required for ZIKV NS5 to r

71 rinsic affinities between Zika virus SLA and NS5, and identified the SLA-binding site on NS5.

72 with binding of the viral IFN-I antagonist, NS5, to prolidase (PEPD), a cellular dipeptidase implica

73 HCV load and anti-c33c and anti-NS5 levels did not distinguish 28 HCV- and HIV-positive

74 ins immunoreacted with 62 to 93% of HCV anti-NS5-positive serum samples.

75 Because NS5 may interfere with both innate and acquired immune r

76 Examination of interactions between NS5 and cellular proteins revealed that NS5 associated w

77 , revealing two-pronged interactions between NS5 and hSTAT2.

78 and 80 nucleotides (nt), respectively, bind NS5 with similar binding affinities.

79 volutionary insights into cap-1 formation by NS5, which underlies innate immunity evasion by flavivir

80 eporter assays showed that IL-8 induction by NS5 was principally through CAAT/enhancer binding protei

81 the initiation of flaviviral replication by NS5.

82 However, the mechanisms utilized by NS5 from different flaviviruses are often quite differen

83 hree nurse shark Ig L chain isotypes, called NS5.

84 A chimeric NS5 containing the D4MT/D4GT and the D2POL domains in th

85 nctional interactions involving the chimeric NS5 protein encoded by the viral genome species is essen

86 POL activities of NS5 WT D2 and the chimeric NS5 proteins with or without the K74I mutation are simil

87 ese ZIKV NS5-hSTAT2 interactions compromised NS5-mediated hSTAT2 degradation and interferon suppressi

88 In contrast, NS5 from Kunjin virus (KUN), a naturally attenuated subt

89 ns-complementation by co-expression of WT D2 NS5 accelerated viral replication of chimeric RNA withou

90 ne mutagenesis of dengue virus type 4 (DEN4) NS5 gene generated a collection of attenuating mutations

91 DENV NS5 polymerase is a promising drug target, as exemplifie

92 at a SUMO interaction motif in ZIKV and DENV NS5 proteins directs nuclear localization.

93 has been demonstrated with ZIKV NS5 and DENV NS5, replacing mSTAT2 with hSTAT2 cannot rescue the YFV

94 We report that like ZIKV NS5 and DENV NS5, YFV NS5 binds human STAT2 (hSTAT2) but not mouse ST

95 has been demonstrated with ZIKV NS5 and DENV NS5, YFV NS5 is unable to interact with hSTAT2 in murine

96 The N-terminal domain of DENV NS5 has guanylyltransferase and methyltransferase (MTase

97 Yet, mutating one DENV NS5 SUMO site (K546R) localized the NS5 mutant to discre

98 We show that DENV NS5 purified from Escherichia coli is a substrate for PK

99 te punctate nuclear bodies (NBs), while DENV NS5 was uniformly dispersed in the nucleoplasm.

100 sm of ZIKV NS5 resembles dengue virus (DENV) NS5 and not its closer relative, Spondweni virus (SPOV).

101 Dengue virus (DENV) NS5 RNA-dependent RNA polymerase (RdRp), an important dr

102 index and represents the first-in-class DENV-NS5 allosteric inhibitor able to target both the virus N

103 tudies showed that the substitution of DENV2 NS5 MTase or POL for DENV4 NS5 within DENV2 RNA resulted

104 he acquired mutations in the DENV2 and DENV4 NS5 MTase or POL domain or in the DENV2 NS3 helicase dom

105 titution of DENV2 NS5 MTase or POL for DENV4 NS5 within DENV2 RNA resulted in a severe attenuation of

106 We reveal that ZIKV NS5 SUMO sites direct NS5 binding to STAT2, disrupt the formation of antiviral

107 ons identified distinct intermediates during NS5 and SLA complex formation.

108 C nonstructural protein 5A (NS5A) and the DV NS5 protein in CD4(+) T cells inhibit HIV replication in

109 Transfection of a plasmid expressing NS5 or a dengue virus replicon induced IL-8 gene express

110 dent RNA polymerase (RdRp) in the flaviviral NS5 protein.

111 the different strategies used by flavivirus NS5 to evade the antiviral effects of IFN-I and how this

112 dinating factors that distinguish flavivirus NS5 proteins.

113 Hence, flavivirus NS5 proteins exhibit a remarkable functional convergence

114 ression is decreased by all human flavivirus NS5 proteins studied.

115 ot inhibited by the expression of flavivirus NS5 protein or by YFV infection, and mumps infection did

116 two alternative conformations of flavivirus NS5 proteins.

117 as a dimer, but the functional evidence for NS5 dimer is lacking.

118 in that undergoes proteolytic processing for NS5 maturation.

119 We found that NS5 SIM sites are required for NS5 nuclear localization and that SUMO sites regulate NS

120 ZIKV NS5 evicts PML from STAT2 NBs, forming NS5/STAT2 NBs that dramatically reduce PML expression in

121 Immune responses to HCV NS5 protein were generated by genetic immunization.

122 However, how NS5 engages SLA is not clear.

123 However, NS5 is also critical to virus replication, contributing

124 ylation in response to IFN, thus identifying NS5 as a potential IFN antagonist.

125 0 contiguous pairs of charged amino acids in NS5 were individually mutagenized to create uncharged pa

126 The serotypic differences in NS5 nuclear localization did not correlate with differen

127 time that there are serotypic differences in NS5 nuclear localization.

128 acids Y25, K28, and K29 that are involved in NS5 oligomerization are essential for localization and i

129 Class 2 mutations resided in NS5 (K61Q in methyltransferase and W751R in RdRp).

130 The linker region of seven residues in NS5, rich in serotype-specific residues, is important fo

131 IKV NS5 SUMO site mutant (K252R) resulted in NS5/STAT2/PML NBs that failed to degrade PML, reduce STA

132 ium concentrations and temperature influence NS5-SLA interactions in solution.

133 Mutation of a single residue in KUN NS5 to the analogous residue in WNV-NY99 NS5 (S653F) ren

134 residue in WNV-NY99 NS5 (S653F) rendered KUN NS5 an efficient inhibitor of pY-STAT1.

135 report the crystal structures of full-length NS5 and its polymerase domain at 3.0 A resolution.

136 of a ternary complex between the full-length NS5 protein from dengue virus, an octameric cap-0 viral

137 there are no structural data for full-length NS5.

138 Here, we demonstrate that the LGTV NS5 JAK-STAT inhibitory domain is contained between amin

139 espite considerable separation on the linear NS5 sequence, these residues localized adjacent to each

140 ing a more distant proximity between the mAb NS5 and mAb 44.1 epitopes.

141 lation of WNV-NS5-E218A, a WNV with a mutant NS5(E218A) protein leads to survival rates and cognitive

142 The nonstructural NS5 proteins of several flaviviruses antagonize IFN-I si

143 levels of inhibition observed for mAbs NS1, NS5, CS6, and CS8.

144 core epitope regions recognized by mAbs NS2, NS5, CS6, CS8, and CS9.

145 and characterization of six mAbs (NS1, NS2, NS5, CS6, CS8, and CS9) that recognize the p22(phox) sub

146 f the DENV nonstructural proteins, with NS3, NS5, and NS1 being dominant in both donor cohorts.

147 Moreover, adenovirus-encoding core and NS3-NS5 proteins increased the secretion of bioactive TGF be

148 Here, we show by competitive NS3-NS5 interaction ELISA that the NS3 peptide spanning resi

149 In contrast, NS3-NS5 protein expression preferentially induced proinflamm

150 o genotype 1-derived HCV antigens (core, NS3-NS5) was examined in 82 patients chronically infected wi

151 nic pools that span the entire HCV core, NS3-NS5.

152 ptide spanning residues 566-585 disrupts NS3-NS5 interaction but not the null-peptide bearing the N57

153 ncoding core and nonstructural proteins (NS3-NS5) were used to express HCV proteins in HSCs.

154 R for the NS3:N570A mutant suggests that NS3-NS5 interaction plays an important role in the balanced

155 ing HCV capsid-E1-E2-NS2-NS3 and HCV NS3-NS4-NS5 in HLA-A2.1-transgenic mice.

156 vity toward either a natural substrate, NS4B-NS5 precursor, or the fluorogenic peptide substrates con

157 ra suggests that phosphorylation of the NS5A/NS5 proteins or their association with cellular kinases

158 KUN NS5 to the analogous residue in WNV-NY99 NS5 (S653F) rendered KUN NS5 an efficient inhibitor of p

159 d efficiency of N region addition (87-93% of NS5 sequences) may be a result not only of simultaneous

160 However, the MT and POL activities of NS5 WT D2 and the chimeric NS5 proteins with or without

161 SIM and SUMO sites determine the assembly of NS5 proteins into discrete nuclear bodies (NBs).

162 acterize the stoichiometry of the complex of NS5 and SLA, and determine how solution conditions such

163 We interpret the multiple conformations of NS5 observed in solution as resulting from weak interact

164 located between the two globular domains of NS5 could be flexible.

165 Therefore, the effect of NS5 on the NS3 NTPase activity was examined.

166 also surprising given that the evolution of NS5 is restrained by the requirement to maintain functio

167 Expression of NS5 alone inhibited STAT1 phosphorylation in response to

168 Thus, the mature form of NS5, when not expressed as a precursor, was able to bind

169 mutation is associated with the function of NS5 in IFN antagonism and may influence virulence of WNV

170 udy, we examined the nuclear localization of NS5 for all four DENV serotypes.

171 ted the differential nuclear localization of NS5.

172 The varied mechanisms of NS5 as an IFN-I antagonist are also surprising given tha

173 The specific amino acid residues of NS5 involved in IFN antagonism are not known.

174 The crystal structure of NS5 shows it as a dimer, but the functional evidence for

175 Available crystal structures of NS5 fragments indicate that residues 263-271 (using the

176 e and that translation inhibition depends on NS5-RNA interaction, primarily through association with

177 NS5, and identified the SLA-binding site on NS5.

178 1a-derived HLA-A2-restricted HCV NS3-1073 or NS5-2594 epitope were generated from a genotype 2a-deriv

179 During ZIKV infection or NS5 expression, we found that ZIKV NS5 evicts PML from S

180 rived from mice immunized with either NS3 or NS5 specifically lysed target cells sensitized to either

181 ecognizing the HCV nonstructural (NS) NS3 or NS5 viral peptide target were examined by mRNA transfect

182 HCV core, but not HCV E1, E2, NS3, NS4, or NS5, bound to STAT1.

183 ation of the latter, indicating that peptide NS5(320-341) engages in specific and discrete interactio

184 n containing an inactivated viral polymerase NS5 (RlucRep-NS5mt).

185 re critical for binding the viral polymerase NS5 to initiate minus-strand RNA synthesis.

186 of the viral genome by the viral polymerase NS5.

187 ractions between the dengue virus polymerase NS5 and SLA in solution has not been performed.

188 -based assays that the viral RNA polymerase, NS5, inhibits translation of the viral genome.

189 m, ZIKV and Dengue virus (DENV) polymerases, NS5 proteins, are predominantly trafficked to the nucleu

190 The viral nonstructural protein NS5 of some flaviviruses functions as the major IFN anta

191 re, we report that the nonstructural protein NS5 of ZIKV and other flaviviruses examined could suppre

192 phalitis virus use the nonstructural protein NS5 to suppress JAK-STAT signaling.

193 rotein NS2a and two in nonstructural protein NS5, to minimize the risk of detection failure due to ge

194 of this pathway is the nonstructural protein NS5.

195 In this study, we show that the purified NS5 alone is sufficient for the synthesis of the two pro

196 To isolate the function of the viral RdRP (NS5) from that of other host or viral factors present in

197 ar localization and that SUMO sites regulate NS5 NB complex constituents, assembly, and function.

198 ng on a novel dominant HLA-B*5502-restricted NS5(329-337) epitope, and assessed T-cell responses to s

199 Our data reveal NS5 SUMO motifs as novel NB coordinating factors that di

200 The relatively stable NS5 region was chosen for analysis because it allowed fo

201 tional significance to the crystal structure NS5 dimer.

202 We found that NS5 SIM sites are required for NS5 nuclear localization

203 As from different serotypes, indicating that NS5 recognizes the overall shape of SLA as well as speci

204 Here, we report that NS5 from the virulent NY99 strain of WNV prevented pY-ST

205 ween NS5 and cellular proteins revealed that NS5 associated with IFN-alpha/beta and -gamma receptor c

206 The results show that NS5 nuclear localization is not strictly required for vi

207 The results show that NS5 stimulated the NS3 NTPase and RTPase activities.

208 Previous studies have shown that NS5 residue Lys-330 is required for interaction between

209 sults of these experiments also suggest that NS5 adopts multiple conformations in solution, ranging f

210 ther cellular and viral MTases suggests that NS5 requires distinct amino acids for its N-7 and 2'-O M

211 The NS5 amplimer/probe set was formulated as a one-tube, mul

212 The NS5 protocol utilizes two flaviviral consensus outer amp

213 The NS5 stimulation of NS3 NTPase was dose-dependent until a

214 The NS5 structure has striking similarities to the NS5 prote

215 e distributed within other regions of E, the NS5 RNA-dependent RNA polymerase (NS5POL) domain, and th

216 sis shows that while the CTLs expressing the NS5-specific TCR reduced HCV RNA replication by a noncyt

217 ors present in the cytoplasmic extracts, the NS5 protein was expressed and purified from Escherichia

218 First, the NS5 methyltransferase and RNA-dependent RNA polymerase (

219 merase chain reaction using primers from the NS5 region of the HGV genome.

220 osorbent assay includes the protein from the NS5 region.

221 249G) together with either a mutation in the NS5 protein (A804V) or three mutations in the 3'UTR (A10

222 nd that five amino acid substitutions in the NS5 protein reduced viral genomic RNA (gRNA) replication

223 teins where there are 6 hinge regions in the NS5 protein, 5 hinge regions in the NS2B bound in the NS

224 acterize mechanism(s) of HIV inhibition, the NS5 proteins of GBV-C, DV, hepatitis C virus, West Nile

225 In this manuscript, we report that like the NS5 proteins of ZIKV and dengue virus (DENV), YFV NS5 pr

226 one DENV NS5 SUMO site (K546R) localized the NS5 mutant to discrete NBs, and NBs formed by the ZIKV N

227 in and suggests that residues 263-268 of the NS5 protein from DENV3 are the major contributors to the

228 rus (HCV) on the antigenic properties of the NS5 protein was studied by using recombinant proteins.

229 se, located at the N-terminal portion of the NS5 protein, to catalyze both guanine N-7 and ribose 2'-

230 to compare the phosphorylation sites of the NS5 proteins of yellow fever virus (YFV) and dengue viru

231 These unique features of the NS5-based immunoassay will be very useful for both clini

232 ze and shape of SLA and the formation of the NS5-SLA complex.

233 with ssRNA for the same binding site on the NS5 polymerase.

234 ased on viral envelope and NS3 proteins, the NS5-based assay (i) reliably discriminates between WNV i

235 Second, the NS5 RdRP domain also binds the amino-terminal domain of

236 us antibody, and RT-PCR assays targeting the NS5 and envelope genes.

237 the C-prM was more sensitive (100%) than the NS5 (91%) or the 3'NC (91%) protocol.

238 We also observe that the NS5-SLA interaction is influenced by the magnesium conce

239 5 structure has striking similarities to the NS5 protein of the related Japanese encephalitis virus.

240 are located at the surface and/or within the NS5 dimer interface, providing a functional significance

241 This NS5-STAT2 interaction requires IFN-I-induced tyrosine ph

242 The activity of this NS5 protein is verified through a de novo RdRp assay on

243 multiple nonstructural proteins ([NS] NS2 to NS5).

244 Impaired CTL responses to NS5 were corrected by syngeneic transfer of control DCs.

245 at a recombinant full-length and a truncated NS5 protein containing the methyltransferase (MTase) dom

246 lting from weak interactions between the two NS5 domains and flexibility of the linker in the absence

247 It is also unclear whether the two NS5 domains interact with each other to form a stable st

248 Dengue virus NS5 also binds SLAs from different serotypes, indicating

249 We show that dengue virus NS5 binds SLA with a 1:1 stoichiometry and that the asso

250 overed allosteric pocket on the dengue virus NS5 polymerase.

251 results indicate a role for the dengue virus NS5 protein in the induction of IL-8 by DEN2V infection.

252 Thus, the dengue virus NS5 protein inhibits HIV replication in vitro, potential

253 To determine whether the dengue virus NS5 protein inhibits HIV replication, CD4(+) T cell line

254 mall-molecule inhibitors of the dengue virus NS5 RNA capping enzyme.

255 HIV replication in dengue virus NS5-expressing cells decreased by >90% compared with con

256 Quantitatively characterizing dengue virus NS5-SLA interactions will facilitate the design and asse

257 eric inhibitor able to target both the virus NS5-NS3 interaction and the host kinases c-Src/Fyn.

258 trate here that the polymerase of the virus, NS5, binds to STAT2 and is necessary and sufficient for

259 gether to block STAT1 phosphorylation, while NS5 binds and promotes degradation of human STAT2, thus

260 e 5' termini of RNA substrates interact with NS5 during the sequential methylation reactions.

261 l as specific interdomain interaction within NS5 required for RNA replication.

262 on prevents pY-STAT1 although a role for WNV NS5 in IFN antagonism has not been fully explored.

263 WNV-NS5-E218A-recovered mice (recovery defined as survival a

264 Hippocampi from WNV-NS5-E218A-recovered mice with poor spatial learning show

265 Inoculation of WNV-NS5-E218A, a WNV with a mutant NS5(E218A) protein leads

266 rescue the YFV NS5-STAT2 interaction, as YFV NS5 is also unable to interact with hSTAT2 in murine cel

267 roteins of ZIKV and dengue virus (DENV), YFV NS5 protein is able to bind hSTAT2 but not murine STAT2

268 es with a lack of IFN-alpha/beta-induced YFV NS5 ubiquitination in murine cells.

269 report that like ZIKV NS5 and DENV NS5, YFV NS5 binds human STAT2 (hSTAT2) but not mouse STAT2 (mSTA

270 demonstrated with ZIKV NS5 and DENV NS5, YFV NS5 is unable to interact with hSTAT2 in murine cells.

271 ur results demonstrate the importance of YFV NS5 in overcoming the antiviral action of IFN-I and offe

272 N-alpha/beta-dependent ubiquitination of YFV NS5 that is required for STAT2 binding in human cells is

273 nique mechanism that involves binding of YFV NS5 to the IFN-activated transcription factor STAT2 only

274 at a lysine in the N-terminal region of YFV NS5.

275 hat interacts with and polyubiquitinates YFV NS5 to promote its binding to STAT2 and trigger IFN-I si

276 Previously, we reported that YFV NS5 requires the presence of type I IFN (IFN-alpha/beta)

277 ing mSTAT2 with hSTAT2 cannot rescue the YFV NS5-STAT2 interaction, as YFV NS5 is also unable to inte

278 rmore, stopped-flow kinetic analysis of Zika NS5-, RdRp- and MTase-SLA interactions identified distin

279 ZIKV NS5 expression resulted in proteasomal degradation of th

280 ZIKV NS5 SUMO sites also transcriptionally regulate cell cycl

281 nuclear localization were required for ZIKV NS5 to regulate hBMEC cell cycle transcriptional respons

282 However, ZIKV NS5 formed discrete punctate nuclear bodies (NBs), while

283 monstrate the function of SUMO sites in ZIKV NS5 NB formation and their importance in regulating nucl

284 We report that like ZIKV NS5 and DENV NS5, YFV NS5 binds human STAT2 (hSTAT2) but

285 These findings establish SUMOylation of ZIKV NS5 as critical in the regulation of antiviral ISG and c

286 a high resolution structure (1.55 A) of ZIKV NS5 methyltransferase bound to a novel S-adenosylmethion

287 The mechanism of ZIKV NS5 resembles dengue virus (DENV) NS5 and not its closer

288 ion of a potential drug-binding site of ZIKV NS5, which might facilitate the development of novel ant

289 ection or NS5 expression, we found that ZIKV NS5 evicts PML from STAT2 NBs, forming NS5/STAT2 NBs tha

290 We reveal that ZIKV NS5 SUMO sites direct NS5 binding to STAT2, disrupt the

291 we report the crystal structure of the ZIKV NS5 protein in complex with S-adenosyl-L-homocysteine, i

292 to discrete NBs, and NBs formed by the ZIKV NS5 SUMO mutant (K252R) were restructured into discrete

293 Expressing the ZIKV NS5 SUMO site mutant (K252R) resulted in NS5/STAT2/PML N

294 Disruption of these ZIKV NS5-hSTAT2 interactions compromised NS5-mediated hSTAT2

295 rary to what has been demonstrated with ZIKV NS5 and DENV NS5, replacing mSTAT2 with hSTAT2 cannot re

296 rary to what has been demonstrated with ZIKV NS5 and DENV NS5, YFV NS5 is unable to interact with hST

297 Although the enzymatic activity of ZikV-NS5 appears to be dispensable, the amino acids Y25, K28,

298 he foundation for therapies that target ZikV-NS5 multimerization and prevent the developmental malfor

299 Here we show that the ZikV-NS5 protein interacts with host proteins at the base of

300 human microcephalic fetal brain tissue, ZikV-NS5 persists at the base of the motile cilia in ependyma