ライフサイエンスコーパス: HDAg

1 HDAg exists in two forms, a small form (S-HDAg) and a la

2 HDAg-L is identical to HDAg-S except that it bears a 19-

3 HDAg-L was found to colocalize with TAP and Aly in the n

4 HDAg-S is required for viral RNA replication, whereas HD

5 Ag-L farnesylation, we found that genotype 3 HDAg-L was inefficiently farnesylated when expressed in

6 eract with the N terminus of TAP, whereas an HDAg-L mutant lacking the NLS failed to interact with fu

7 primer extension (SHAPE) applied to free and HDAg-bound HDV RNAs indicated that the characteristic se

8 containing the 10-amino acid TAT peptide and HDAg-L(198-210), inhibited the interaction between HDAg-

9 ue to a weak interaction between the RNA and HDAg.

10 The roles of these two forms, HDAg-S and HDAg-L, are opposed.

11 is associated with hepatitis delta antigen (HDAg) in cells replicating HDV.

12 mine the effects of hepatitis delta antigen (HDAg) on the ribozyme activities of HDV RNA in vivo.

13 rus-encoded protein hepatitis delta antigen (HDAg) perform essential roles in the viral life cycle, i

14 ture of HDV RNA and hepatitis delta antigen (HDAg), a basic, disordered, oligomeric protein.

15 in the presence of hepatitis delta antigen (HDAg), and in the presence of transcription factor IIF (

16 sole viral protein, hepatitis delta antigen (HDAg), from the same open reading frame.

17 the viral protein, hepatitis delta antigen (HDAg), in HDV RNA replication are similar for both genot

18 ly encoded protein, hepatitis delta antigen (HDAg), in infected cells; however, the nature of the rib

19 whose product, the hepatitis delta antigen (HDAg), is expressed in two isoforms, small (S-HDAg) and

20 ncodes two forms of hepatitis delta antigen (HDAg), small HDAg (HDAg-S), which is required for viral

21 the viral protein, hepatitis delta antigen (HDAg), to be synthesized from a single open reading fram

22 s a single protein, hepatitis delta antigen (HDAg), which is required for viral replication.

23 in the presence of hepatitis delta antigen (HDAg), which is the only protein encoded by HDV RNA, the

24 sole viral protein, hepatitis delta antigen (HDAg).

25 d mRNA encoding the hepatitis delta antigen (HDAg).

26 cipal gene product, hepatitis delta antigen (HDAg).

27 the sequence of the hepatitis delta antigen (HDAg).

28 s a single protein, hepatitis delta antigen (HDAg).

29 The large hepatitis delta antigen (HDAg-L) mediates hepatitis delta virus (HDV) assembly an

30 ntigen (HDAg-S) and the large delta antigen (HDAg-L), from a single open reading frame.

31 essential proteins, the small delta antigen (HDAg-S) and the large delta antigen (HDAg-L), from a sin

32 The small hepatitis delta antigen (HDAg-S) is expressed throughout replication and is neede

33 bsence of the small hepatitis delta antigen (HDAg-S).

34 [HBeAg] negative, anti-hepatitis D antigen [HDAg] positive, and HDV RNA positive, with serum HBsAg c

35 tains two types of hepatitis delta antigens (HDAg) in the virion.

36 (198-210), inhibited the interaction between HDAg-L and TAP and blocked HDV virion assembly and secre

37 Both HDAgs contain a nuclear localization signal (NLS), but o

38 (i) Both HDAgs, particularly LHDAg, enhanced the self-cleavage ac

39 iii) The enhancement of ribozyme activity by HDAg does not require HDV RNA replication.

40 re that allows RNA bending and condensing by HDAg.

41 vities of HDV ribozyme also were enhanced by HDAg.

42 hat nuclear import of HDV RNA is mediated by HDAg.

43 ion of the HDV RNA polyadenylation signal by HDAg.

44 d suppression of the polyadenylation site by HDAg may not significantly regulate the synthesis of the

45 ith HDAg-L, but not with an export-defective HDAg-L mutant, in which Pro(205) was replaced by Ala.

46 Methylation-defective HDAg lost the ability to form a speckled structure in th

47 which is associated with severe HDV disease, HDAg-L strongly inhibits editing of a nonreplicating gen

48 Thirty-three distinct HDAg sequences from subtypes I, II, and III were tested

49 a numerous contacts between the RNA and each HDAg monomer.

50 a general association with membranes enables HDAg to inhibit replication.

51 n of HDV RNA synthesis, mostly due to excess HDAg-L production.

52 in vitro using native, bacterially expressed HDAg have been hampered by a lack of specificity for HDV

53 ding experiments using bacterially expressed HDAg showed that the formation of a minimal ribonucleopr

54 he presence or absence of elongation factors HDAg and TFIIF.

55 ltimeric binding is not limited to the first HDAg bound and that a minimum RNA length of between 604

56 that were mutated so as to be defective for HDAg production.

57 Here, the specific RNA features required for HDAg binding and the topology of the complexes formed we

58 The large form (HDAg-L) is farnesylated, is expressed only at later time

59 l protein hepatitis delta antigen long form (HDAg-L), which is necessary for viral particle productio

60 leads to the production of the longer form (HDAg-L), which is required for RNA packaging but which i

61 The roles of these two forms, HDAg-S and HDAg-L, are opposed.

62 e pressures on the hepatitis D antigen gene (HDAg).

63 For both genotypes, HDAg was able to support replication of RNAs of the same

64 uired for viral replication, and large HDAg (HDAg-L), which is essential for viral assembly.

65 hepatitis delta antigen (HDAg), small HDAg (HDAg-S), which is required for viral replication, and la

66 Here, HDAg-L proteins from different HDV genotypes and genotyp

67 However, HDAg was found to suppress editing at the amber/W site w

68 self-cleavage activity of HDV RNA; however, HDAgs are not required for HDV RNA cleavage.

69 (ii) HDAg could not restore the ribozyme activity of mutant H

70 The inability of genotype III HDAg to support replication of genotype I RNA could have

71 however, neither genotype I nor genotype III HDAg was able to support replication of such mutated RNA

72 of the core arginines of ARM I or ARM II in HDAg-160 did not diminish binding to HDV unbranched rodl

73 A mutation in HDAg-L and a farnesyl transferase inhibitor were both us

74 About 11% of codon sites in HDAg were estimated to be under diversifying selection.

75 While increased HDAg-L production was the primary mechanism of inhibitio

76 uding both the 1.7-kb HDV RNA and the 0.8-kb HDAg mRNA, from the genomic-sense RNA was surprisingly r

77 ion is initiated from an RNA template, and L-HDAg appears only late in the replication cycle, it rema

78 ence of almost equal amounts of S-HDAg and L-HDAg in the virion raised a puzzling question concerning

79 forms of hepatitis delta antigens (S- and L-HDAg), respectively.

80 The large form of hepatitis delta antigen (L-HDAg), which is responsible for virus packaging, was not

81 mulation of large hepatitis delta antigen (L-HDAg).

82 nsfection of plasmid cDNAs expressing both L-HDAg and HDV RNA results in a potent inhibition of HDV R

83 , it was not due to possible inhibition by L-HDAg, as HDV-S RNA replication was not affected when bot

84 as surprisingly resistant to inhibition by L-HDAg.

85 V RNA replication, whereas the large form (L-HDAg) potently inhibits it by a dominant-negative inhibi

86 s, a small form (S-HDAg) and a large form (L-HDAg).

87 in two isoforms, small (S-HDAg) and large (L-HDAg).

88 ed when a mutant HDV genome unable to make L-HDAg was used, suggesting that L-HDAg did not play a rol

89 w HDV can escape the inhibitory effects of L-HDAg and initiate RNA replication after infection.

90 genome is complexed with equal amounts of L-HDAg and S-HDAg.

91 r examined the effect of overexpression of L-HDAg at various stages of the HDV replication cycle, sho

92 mediates, we showed that a small amount of L-HDAg is sufficient to inhibit HDV genomic RNA synthesis

93 udy, we examined the inhibitory effects of L-HDAg on the synthesis of various HDV RNA species.

94 this study, we investigated the effect of L-HDAg, produced as a result of the natural HDV RNA editin

95 mutant HDV RNA genome unable to synthesize L-HDAg was still exported.

96 ken together, these results indicated that L-HDAg affects neither the rate of HDV RNA synthesis nor t

97 e to make L-HDAg was used, suggesting that L-HDAg did not play a role.

98 nal steady-state level of HDV RNA and that L-HDAg is unlikely to act as an inhibitor of HDV RNA repli

99 We found that L-HDAg was aggregated in specific nuclear domains and that

100 ttransfection and in the wild type and the L-HDAg-deficient mutant.

101 d that, contrary to conventional thinking, L-HDAg alone, at a certain molar ratio with HDV RNA, can i

102 Thus, L-HDAg does not inherently inhibit HDV RNA synthesis.

103 ng that HDV RNA synthesis was resistant to L-HDAg when it was overexpressed 3 days after HDV RNA repl

104 Further, when L-HDAg expression from HDV-L RNA was abolished by site-dir

105 esis of these RNAs was inhibited only when L-HDAg was in vast excess over S-HDAg.

106 lication cycle, it remains unclear whether L-HDAg can modulate HDV RNA replication in the natural HDV

107 is required for replication of HDV, while L-HDAg inhibits viral replication and is required for the

108 They also explain why L-HDAg is not produced early in HDV infection, despite the

109 from introduced plasmids, colocalizes with L-HDAg and the transcriptional repressor PML.

110 is required for viral replication, and large HDAg (HDAg-L), which is essential for viral assembly.

111 iated proteins like PML were found in larger HDAg complexes that had developed into apparently hollow

112 s did not abolish the ability of full-length HDAg to inhibit HDV RNA editing in cells, an activity th

113 Mutant HDAg proteins defective for multimerization exhibited ne

114 In contrast, although myristoylated HDAg-S was incorporated into VLPs far more efficiently t

115 e efficiently than HDAg-S or nonfarnesylated HDAg-L, it was incorporated far less efficiently than wi

116 Neither viral replication nor HDAg was required for the highly specific editing observ

117 tor were both used to abolish the ability of HDAg-L to inhibit replication.

118 hich replication can occur in the absence of HDAg-L.

119 removal of the C-terminal 35 amino acids of HDAg yields a native, bacterially expressed protein, HDA

120 The clear genotype-specific activity of HDAg in supporting HDV RNA replication confirms the orig

121 (iv) RNA-binding activity of HDAg is required for the enhancement of RNA cleavage.

122 The nuclear export activity of HDAg-L is important for HDV particle formation.

123 equired for the RNA-transporting activity of HDAg.

124 ry RNA sequence, is the major determinant of HDAg RNA binding specificity.

125 Disruption of HDAg multimerization by site-directed mutagenesis was fo

126 The C-terminal domain of HDAg-L was shown to directly interact with the N terminu

127 tion of TAP or Aly reduced nuclear export of HDAg-L and assembly of HDV virions.

128 Ag-L was increased, so too was the extent of HDAg-L farnesylation for all three genotypes.

129 sing a novel assay to quantify the extent of HDAg-L farnesylation, we found that genotype 3 HDAg-L wa

130 he HDV genotype III RNA and the two forms of HDAg.

131 RNA may be the first biological function of HDAg in the HDV life cycle.

132 g protein A (DIPA), is a cellular homolog of HDAg.

133 HDAg), but not the small (SHDAg), isoform of HDAg has the capacity to activate the expression of cotr

134 This mutant expressed elevated levels of HDAg-L early during replication, and at later times, its

135 However, the mechanisms of HDAg-L-mediated nuclear export of HDV ribonucleoprotein

136 uding the phosphorylation and methylation of HDAg.

137 rich motifs (ARMs I and II) in the middle of HDAg.

138 ed a novel posttranslational modification of HDAg and indicated its importance for HDV RNA replicatio

139 hat both the NLS and an RNA-binding motif of HDAg are required for the RNA-transporting activity of H

140 zation signal (NLS) or RNA-binding motifs of HDAg resulted in the failure of nuclear import of HDV RN

141 In the presence of HDAg and SII, pausing is observed without stimulation of

142 creased in parallel, even in the presence of HDAg.

143 n-amber/W sites and subsequent production of HDAg variants that acted as trans-dominant inhibitors of

144 However, as the intracellular ratio of HDAg-S to HDAg-L was increased, so too was the extent of

145 s indicate that the amino-terminal region of HDAg is in close contact with the RNA and that the propo

146 d conclusive determination of the regions of HDAg involved in RNA binding.

147 sent study specifically examines the role of HDAg multimerization in the formation of the HDV ribonuc

148 nt mutations within the carboxyl terminus of HDAg-L were screened, and three mutants that severely in

149 is limited to a small number of epitopes on HDAg.

150 nuclear localization signal (NLS), but only HDAg-L contains a CRM1-independent nuclear export signal

151 the hepatitis delta virus RNAs and protein, HDAg, perform critical roles in virus replication.

152 lds a native, bacterially expressed protein, HDAg-160, that specifically binds HDV unbranched rod RNA

153 when expressed naturally during replication, HDAg-L is able to inhibit replication and thereby inhibi

154 UGG (tryptophan [W]) codon in the resulting HDAg-L message.

155 S-HDAg can transactivate HDV RNA replication.

156 S-HDAg is required for replication of HDV, while L-HDAg in

157 complexed with equal amounts of L-HDAg and S-HDAg.

158 HDAg exists in two forms, a small form (S-HDAg) and a large form (L-HDAg).

159 The small form (S-HDAg) is required for HDV RNA replication, whereas the l

160 An R13A mutation in S-HDAg inhibited HDV RNA replication.

161 We further found that the methylation of S-HDAg affected its subcellular localization.

162 r, the presence of almost equal amounts of S-HDAg and L-HDAg in the virion raised a puzzling question

163 uch as phosphorylation and acetylation, of S-HDAg can modulate HDV RNA replication.

164 The methylation of S-HDAg is essential for HDV RNA replication, especially fo

165 ate was not due to insufficient amounts of S-HDAg, as identical results were obtained in a cell line

166 d only when L-HDAg was in vast excess over S-HDAg.

167 d in a cell line that stably overexpresses S-HDAg.

168 DAg), is expressed in two isoforms, small (S-HDAg) and large (L-HDAg).

169 Here we show that S-HDAg can be methylated by protein arginine methyltransfe

170 rms of hepatitis delta antigen (HDAg), small HDAg (HDAg-S), which is required for viral replication,

171 ion, a majority of human hepatocytes stained HDAg-positive long before HBV spreading was completed, c

172 These data suggest HDAg may regulate amber/W site editing during virus repl

173 Furthermore, a peptide, TAT-HDAg-L(198-210), containing the 10-amino acid TAT peptid

174 rporated into VLPs far more efficiently than HDAg-S or nonfarnesylated HDAg-L, it was incorporated fa

175 The results unambiguously demonstrate that HDAg binds HDV RNA as a multimer and that the HDAg multi

176 Our results indicate that HDAg does not recognize the primary sequence of the RNA;

177 e results confirm the previous proposal that HDAg binds as a large multimer and demonstrate that the

178 We have further shown that HDAg, via its NLS, interacts with karyopherin alpha2 in

179 These results suggest that HDAg can regulate the cleavage and ligation of HDV RNA d

180 bout 300 nucleotides (nt) and suggested that HDAg binds the RNA as a multimer of fixed size.

181 Thus, a switch from production of the HDAg mRNA to the full-length HDV RNA does not occur in t

182 significantly regulate the synthesis of the HDAg mRNA, as previously proposed.

183 vitro, suggesting that nuclear import of the HDAg-HDV RNA complex is mediated by the karyopherin alph

184 DAg binds HDV RNA as a multimer and that the HDAg multimer is formed prior to binding the RNA.

185 esylation of the cysteine residue within the HDAg-L carboxyl terminus is required for both functions.

186 to genotype-specific differences within the HDAg-L carboxyl terminus.

187 t the adenosine to an inosine (I) within the HDAg-S amber codon in antigenomic RNA.

188 ucture of the RNA is preserved when bound to HDAg.

189 HDAg-L is identical to HDAg-S except that it bears a 19-amino acid extension at

190 contribution of unpaired bases in HDV RNA to HDAg binding is to allow flexibility in the unbranched q

191 ver, as the intracellular ratio of HDAg-S to HDAg-L was increased, so too was the extent of HDAg-L fa

192 rporated far less efficiently than wild-type HDAg-L; thus, farnesylation was required for efficient a

193 binding activity was analyzed in vitro using HDAg-160, a C-terminal truncation that binds with high a

194 When HDAg-L is artificially expressed at the onset of replica

195 Finally, it was observed that when HDAg-S was artificially myristoylated, it could efficien

196 required for viral RNA replication, whereas HDAg-L, which is produced as a result of editing, inhibi

197 ver, there is controversy concerning whether HDAg-L expressed naturally at later times as a consequen

198 results are consistent with a model in which HDAg binds HDV unbranched rod RNA as multimers of fixed

199 replicating genotype III reporter RNA, while HDAg-S inhibits only when expressed at much higher level

200 lex TAP-Aly was found to form a complex with HDAg-L, but not with an export-defective HDAg-L mutant,

201 A cellular gene whose product interacts with HDAg has now been identified, and this interaction was f

202 ys, a combinatorial effect not observed with HDAg and SII.

203 normally are closely linked separate within HDAg-associated complexes.