ライフサイエンスコーパス: vIRF

1 vIRF also suppresses genes under IFN regulatory control

2 vIRF does not compete with IRF-1 for binding to DNA or c

3 vIRF inhibits IFN-beta signal transduction as measured u

4 vIRF-1 interaction domain was localized between amino ac

5 vIRF-3 is a KSHV latent gene that is critical for prolif

6 vIRF-3, also called LANA2, is a latently expressed nucle

7 roduct viral interferon regulatory factor 1 (vIRF-1) is targeted to mDRM during virus replication and

8 ncoded viral interferon regulatory factor 1 (vIRF-1) promotes mitochondrial clearance by activating m

9 viral interferon (IFN) regulatory factor 1 (vIRF-1).

10 The ORF K9, viral IRF 1 (vIRF-1), has been cloned, and it was shown that, when ov

11 eins as neighboring proteins of viral IRF-1 (vIRF-1) and vIRF-4 during viral reactivation, and 47 pro

12 Three of them, viral IRF-1 (vIRF-1), vIRF-2, and vIRF-3, have been cloned and found,

13 t of others, such as K4.1 (vMIP-III), K11.1 (vIRF-2), and K10.5 (LANA2, vIRF-3), was inhibited.

14 Three of them, viral IRF-1 (vIRF-1), vIRF-2, and vIRF-3, have been cloned and found, when ove

15 Thus, in contrast to vIRF-1, vIRF-3 neither blocks the interaction between IRF-3 and

16 The mRNA for LANA-2/vIRF-3 is similarly resistant to viral reactivation.

17 While HHV-8 vIRF-4 is known to interact physically with USP7 deubiqu

18 A vIRF transcript of 1.7 kb in size was detected in low le

19 first examples of vIRF ubiquitination and a vIRF substrate of USP7, enhanced expression of vIRF-4 vi

20 he work shown here is the first example of a vIRF being associated with either the KSHV or RRV virion

21 ng of RNA extracted from BCBL-1 cells with a vIRF-3-specific probe and reverse transcription-PCR anal

22 In addition to its co-repressor activity, vIRF-3 can also act as a transcriptional activator on ge

23 Although vIRF-3 is not a DNA-binding protein, it is recruited to

24 by a mechanism involving caspase-3, although vIRF-2 itself is not pro-apoptotic.

25 Two of these homologues, vIRF-1 and vIRF-2, were previously identified and functionally anal

26 ffusion lymphoma (PEL) cells, and vIRF-1 and vIRF-3 have been reported to promote PEL cell viability.

27 rotease 7 (USP7); interactions of vIRF-1 and vIRF-3 with USP7 promote PEL cell viability and regulate

28 hboring proteins of viral IRF-1 (vIRF-1) and vIRF-4 during viral reactivation, and 47 proteins were s

29 RAFs by vIRF-2, and activities of vIRF-2 and vIRF-2-USP7 interaction in HHV-8 latent and lytic biolog

30 e of them, viral IRF-1 (vIRF-1), vIRF-2, and vIRF-3, have been cloned and found, when overexpressed,

31 e no binding between the full-size IRF-3 and vIRF-1 could be detected by the same assay, we show that

32 These studies illustrate that vIRF-3 and vIRF-1 have clearly distinct functions.

33 n primary effusion lymphoma (PEL) cells, and vIRF-1 and vIRF-3 have been reported to promote PEL cell

34 viral proteins, ORF17, thymidine kinase, and vIRF-4.

35 tation, and targeted mutagenesis approaches, vIRF-2 was determined to promote latent PEL cell viabili

36 terferon regulatory factors (IRFs), known as vIRFs.

37 , for the first time, of a virion-associated vIRF.

38 e coadaptor CREB-binding protein (CBP) binds vIRF and synergizes transactivation of MYC, but, unexpec

39 dependent of the DNA binding domains of both vIRF and IRF-1.

40 iously identified IBiD domain, to which both vIRF-1 and IRF-3 bind.

41 on, while lytic replication was inhibited by vIRF-2, in part or in whole via USP7 interaction.

42 for negative-feedback regulation of MAVS by vIRF-1 during virus replication.

43 gulated negatively by USP7 and positively by vIRF-2-USP7 interaction, the latter competing for USP7-T

44 mediator TRAF3 was found to be suppressed by vIRF-4 in a USP7-binding-associated manner in infected c

45 ase, associated activation of these TRAFs by vIRF-2, and activities of vIRF-2 and vIRF-2-USP7 interac

46 ogene is required for cell transformation by vIRF, and that vIRF increases MYC transcription up to 15

47 tent and lytic infection, and is targeted by vIRFs 1, 3, and 4.

48 viral homologs of the cellular IRFs, called vIRFs.

49 In this study, we have further characterized vIRF-2 and shown that it is a nuclear protein which is c

50 As a consequence, vIRF efficiently prevents p53-mediated apoptosis.

51 As a consequence, vIRF expression markedly alters cellular cytokine expres

52 Consequently, vIRF-3 stimulates the IRF-3- and IRF-7-mediated activati

53 that contain regulatory elements controlling vIRF transcription.

54 inant virus with all 8 of the vIRFs deleted (vIRF-ko RRV).

55 These results demonstrate vIRF as a KSHV early gene, identify its promoter and def

56 have characterized a novel gene, designated vIRF-3, encoded within the previously predicted ORF K10.

57 -HHV-8 agents, such as those able to disrupt vIRF-4-USP7 interaction or vIRF-4-stabilizing USP7 activ

58 to block IFN mediated by TLRs but that each vIRF has a unique function and mechanism for blocking an

59 resent study demonstrates that HHV-8-encoded vIRF-1 targets to the mitochondrial detergent-resistant

60 homology to cellular IRF-4 and HHV-8-encoded vIRF-2 and K11.

61 The KSHV gene ORF K9 encodes vIRF which is a protein with low but significant homolog

62 results suggest that the latently expressed vIRF-2 has a role in viral mimicry which targets the act

63 Stable transfectant NIH3T3 clones expressing vIRF grew in soft agar and at low serum concentrations,

64 Viral interferon regulatory factor (vIRF) encoded by Kaposi's sarcoma-associated herpesvirus

65 Viral interferon regulatory factor (vIRF) encoded by Kaposi's sarcoma-associated herpesvirus

66 IP-1 and eight interferon regulatory factor (vIRF) homologues compared to three MIP-1 and four vIRF h

67 a viral interferon (IFN) regulatory factor (vIRF) which functions as a repressor for cellular IFN-me

68 ncodes a viral interferon regulatory factor (vIRF) which functions as a repressor for cellular interf

69 encodes viral interferon regulatory factor (vIRF), a gene product that has homology to the IRF famil

70 es four viral interferon regulatory factors (vIRFs 1 to 4), all of which are expressed during lytic r

71 pattern of the viral IFN-regulatory factors (vIRFs) encoded by KSHV.

72 mily of viral interferon regulatory factors (vIRFs).

73 NK1) and MAVS, was found to be important for vIRF-1 association with mitochondria.

74 HV-8 productive replication and, indeed, for vIRF-4 expression and reveals a new function of vIRF-4 v

75 s of USP7 targeting have been identified for vIRFs 1-3, the significance of the interaction of vIRF-4

76 homologues compared to three MIP-1 and four vIRF homologues in KSHV.

77 Furthermore, vIRF-3 contributes to KSHV-associated pathogenesis by st

78 Kaposi sarcoma-associated herpesvirus vIRF is a viral transcription factor that inhibits inter

79 four interferon regulatory factor homologs, vIRFs 1-4, that interact with and inhibit various mediat

80 th LANA in KS, in contrast to its homologue, vIRF-3/LANA-2, which is transcribed only in KSHV-associa

81 Two of these homologues, vIRF-1 and vIRF-2, were previously identified and functi

82 The presented data are the first to identify vIRF-2 targeting of USP7 and its role in HHV-8 biology,

83 uitination and, in infected cells, increased vIRF-4 expression.

84 monstrate that during de novo RRV infection, vIRFs are inhibiting the induction of IFN at the transcr

85 Recent characterization of a viral IRF (vIRF) deletion clone of RRV (vIRF-knockout RRV [vIRF-ko

86 Thus, KSHV encodes a viral IRF (vIRF)-2 protein, sharing homology with cellular IRFs and

87 ulatory factors (IRFs), known as viral IRFs (vIRFs), participate in evasion of the host interferon (I

88 egulatory factors (IRFs), termed viral IRFs (vIRFs).

89 ulatory factors (IRFs), known as viral IRFs (vIRFs).

90 egulatory factors (IRFs), termed viral IRFs (vIRFs).

91 ), ORF 72 (vCyclin), ORF 74 (vGPCR), and K9 (vIRF-1), was unaffected by the presence of CDV, while th

92 We demonstrate that KSHV vIRF directly interacts with cellular transcriptional co

93 These results demonstrate that KSHV vIRF interacts with and inhibits the p300 transcriptiona

94 These results suggest that KSHV vIRF interacts with and inhibits the p53 tumor suppresso

95 Here, we demonstrate that KSHV vIRF interacts with the cellular p53 tumor suppressor th

96 ral response and the mechanism by which KSHV vIRF-2 inhibits this innate response.

97 is a common characteristic of the four KSHV vIRFs and that p53 is indeed a key factor in the host's

98 All four KSHV vIRFs inhibit the induction of IFN, while vIRF1 and vIRF

99 vMIP-III), K11.1 (vIRF-2), and K10.5 (LANA2, vIRF-3), was inhibited.

100 Moreover, vIRF-1 binds directly to a mitophagy receptor, NIX, on t

101 Moreover, vIRF-3 can stabilize the c-Myc protein by increasing its

102 The ability of vIRF to block IRF-1-mediated transcription is independen

103 s in normal IRF-3 turnover in the absence of vIRF-2, during the antiviral response induced by poly(I:

104 Tis represses the promoter activities of vIRF and heterologous herpes simplex virus thymidine kin

105 of these TRAFs by vIRF-2, and activities of vIRF-2 and vIRF-2-USP7 interaction in HHV-8 latent and l

106 with USP7, and TRAF3-inhibitory activity of vIRF-4.

107 nsfection, but the functional consequence of vIRF-1 that is expressed during infection with HHV-8 is

108 her, our data identify the first examples of vIRF ubiquitination and a vIRF substrate of USP7, enhanc

109 We further show that ectopic expression of vIRF-1 in NIH 3T3 cells confers resistance to tumor necr

110 We found that the expression of vIRF-2 in HEK293 cells inhibited the antiviral effect of

111 USP7 is necessary for optimal expression of vIRF-4 and normal HHV-8 replication.

112 RF substrate of USP7, enhanced expression of vIRF-4 via its interaction with USP7, and TRAF3-inhibito

113 , likely via binding-regulated expression of vIRF-4.

114 on and associated signaling as a function of vIRF-4 and its interaction with USP7 identified a role o

115 F-4 expression and reveals a new function of vIRF-4 via inhibition of the activity of TRAF3, a pivota

116 Thus, the anti-interferon functions of vIRF-2 may contribute to the establishment of a chronic

117 iological significance of the interaction of vIRF-4 with USP7 and reveal a mechanism of vIRF-4-mediat

118 1-3, the significance of the interaction of vIRF-4 with USP7 has remained undetermined.

119 -specific protease 7 (USP7); interactions of vIRF-1 and vIRF-3 with USP7 promote PEL cell viability a

120 Genetic and pharmacological interruption of vIRF-1/NIX-activated mitophagy inhibits HHV-8 productive

121 t the transient expression of high levels of vIRF-1 is inadequate to subvert many of the antiviral ef

122 The low levels of vIRF-1 that were associated with PML bodies were insuffi

123 infected with HHV-8 expressed low levels of vIRF-1 that were associated with PML bodies, whereas muc

124 High levels of vIRF-1 were expressed for only a short period during the

125 whereas cells that expressed high levels of vIRF-1 were resistant to some changes induced by IFN-alp

126 th PML bodies, whereas much higher levels of vIRF-1 were transiently expressed during the lytic phase

127 Nuclear localization of vIRF-2 was confirmed by in situ detection of ectopically

128 f vIRF-4 with USP7 and reveal a mechanism of vIRF-4-mediated innate-immune evasion and pro-replicatio

129 Similarly, the overexpression of vIRF-3 in mouse L929 cells resulted in inhibition of vir

130 The presence of vIRF-3 in the enhanceosome assembled on the IFNA promote

131 r through the putative DNA binding region of vIRF and the central region of p53.

132 The N-terminal region of vIRF-1 interacts directly with membrane lipids, includin

133 ranscriptional silencer in the regulation of vIRF gene expression.

134 in interactions as well as the repression of vIRF promoter activity.

135 Our findings uncover an essential role of vIRF-1 in mitophagy activation and promotion of HHV-8 ly

136 d gene 15 (ISG 15) promoter, and the role of vIRF-1 in viral mimicry was implied.

137 egion in the upstream regulatory sequence of vIRF gene.

138 e and USP7-binding-associated suppression of vIRF-4 ubiquitination and, in infected cells, increased

139 ition, a GxRP motif within the N terminus of vIRF-1, conserved in the mDRM-targeting region of mitoch

140 infected cells identified ubiquitination of vIRF-4 via K48-linkage and USP7-binding-associated suppr

141 are the first to validate the importance of vIRFs during de novo infection in the host.

142 To assess the role of vIRFs during de novo infection, we have utilized the bac

143 ses, this study has investigated the role of vIRFs in viral replication and the development of the im

144 e able to disrupt vIRF-4-USP7 interaction or vIRF-4-stabilizing USP7 activity.

145 e regulation, a property not shared by other vIRFs.

146 mology and similar genomic location to other vIRFs, vIRF4 is distinctive, as it does not target and a

147 nguishable from USP7 interactions with other vIRFs and other proteins, that this interaction modulate

148 Additionally, cells overexpressing vIRF-3 exhibit higher levels of c-Myc ubiquitylation, su

149 re, MAVS, which has the potential to promote vIRF-1 targeting to mDRM possibly by inducing cardiolipi

150 expressed enhanced green fluorescent protein/vIRF-2 fusion protein.

151 er of open reading frames encoding proteins (vIRFs) with homology to the cellular transcription facto

152 ansfection assays with the IFNACAT reporter, vIRF-3 functioned as a dominant-negative mutant of both

153 Consistent with these results, vIRF-1 targeting to mDRM contributes to promotion of HHV

154 RRV vIRF R6 can inhibit the induction of IFN by IRF3; howeve

155 ate the immunomodulatory mechanism of an RRV vIRF and its ability to assist the virus in rapid immune

156 Our work elucidates the role of one RRV vIRF, R12, and demonstrates that RRV can dampen the type

157 We found that RRV vIRF R6, when expressed ectopically, interacts with a tr

158 r present study, we demonstrate that the RRV vIRF R12 aids viral replication in the presence of the t

159 F3; however, it is not known whether any RRV vIRFs inhibit ISG induction following IFN receptor signa

160 echanisms behind immunomodulation by the RRV vIRFs during infection.

161 Less is known about the RRV vIRFs.

162 of a viral IRF (vIRF) deletion clone of RRV (vIRF-knockout RRV [vIRF-ko RRV]) demonstrated that vIRFs

163 F) deletion clone of RRV (vIRF-knockout RRV [vIRF-ko RRV]) demonstrated that vIRFs inhibit induction

164 Since vIRF is primarily expressed in KSHV-infected B cells, no

165 ransferases p300 and P/CAF potently suppress vIRF transactivation.

166 l homologs of IFN regulatory factors (termed vIRFs) that can manipulate the host immune response by m

167 s of cellular IFN regulatory factors, termed vIRFs, which are hypothesized to help these viruses evad

168 ed for cell transformation by vIRF, and that vIRF increases MYC transcription up to 15-fold through s

169 signaling proteins TRAF3 and TRAF6, and that vIRF-2 targeting of USP7 regulates HHV-8 productive repl

170 F-4-USP7 interaction in infected cells, that vIRF-4 association with USP7 is necessary for optimal ex

171 We demonstrate that vIRF inhibits responses to type I and type II interferon

172 These results demonstrate that vIRF-1 can modulate the transcription of the IFNA genes

173 Here we demonstrate that vIRF-3 directly interacts with cellular interferon regul

174 ism of this effect we have demonstrated that vIRF-2 physically interacts with PKR consequently inhibi

175 These studies illustrate that vIRF-3 and vIRF-1 have clearly distinct functions.

176 Collectively, these results indicate that vIRF-3 can effectively manipulate c-Myc stability and fu

177 gative ISRE-binding protein, indicating that vIRF acts together with a cellular cofactor at the PRF e

178 ter injection into nude mice indicating that vIRF has the properties of a viral oncogene.

179 Here, we report that vIRF-2 also interacts with USP7, via a means distinguish

180 Here, we report that vIRF-2 also targets USP7, utilizing a PSTS motif matchin

181 g of the vIRF-3 binding domain revealed that vIRF-3 associates with both IRF-3 and IRF-7 through its

182 re, we extend this observation and show that vIRF-1 also downregulates the transcriptional activity o

183 be detected by the same assay, we show that vIRF-1 also targets the carboxy-terminal region (aa 1623

184 Here, we show that vIRF-2 mediates IRF-3 inactivation by a mechanism involv

185 In this study, we show that vIRF-3 binds to the F-box of Skp2 and recruits it to c-M

186 Here we show that vIRF-3 can associate with Skp2, a key component of the S

187 These data suggest that vIRF may contribute to viral pathogenesis and cellular t

188 These results suggest that vIRF-1 is the first example of a viral protein to inhibi

189 t KS spindle cells, this study suggests that vIRF is a transforming oncogene active in B cell neoplas

190 nockout RRV [vIRF-ko RRV]) demonstrated that vIRFs inhibit induction of type I and type II IFNs durin

191 These findings reveal the broad impact that vIRFs have on pathogenesis and the immune response in vi

192 Altogether, this report indicates that vIRFs are able to block IFN mediated by TLRs but that ea

193 The vIRF genes are arranged in tandem but differ in function

194 The vIRF-1/K9 clustered with LANA in KS, in contrast to its

195 The vIRF-3 mRNA levels in BCBL-1 cells were increased upon 1

196 The vIRF-3 ORF encodes a 73-kDa protein with homology to cel

197 We had previously characterized the vIRF core promoter and defined a 12-O-tetradecanoylphorb

198 acterized the mRNA expression pattern of the vIRF gene and its promoter.

199 The product of the vIRF-1 gene blocks responses to IFN when overexpressed b

200 The mapping of the vIRF-3 binding domain revealed that vIRF-3 associates wi

201 ere we show, through genetic ablation of the vIRF-4-USP7 interaction in infected cells, that vIRF-4 a

202 ugh the generation of a KSHV mutant with the vIRF gene deleted.

203 A cellular protein targeted by all the vIRFs is ubiquitin-specific protease 7 (USP7); while rep

204 nerate a recombinant virus with all 8 of the vIRFs deleted (vIRF-ko RRV).

205 other mediators of antiviral signaling, the vIRFs are believed to be essential for productive replic

206 Thus, in contrast to vIRF-1, vIRF-3 neither blocks the interaction between IR

207 and 47 proteins were shared between the two vIRFs; the list also includes three viral proteins, ORF1

208 This suggests that the various vIRFs encoded by KSHV are important for KSHV latency as

209 While vIRF-1 is unable to bind DNA with the same specificity a

210 ha production in PBMC cultures infected with vIRF-ko RRV than in cultures infected with WT(BAC) RRV.

211 Moreover, in vivo infection with vIRF-ko RRV resulted in earlier and sustained production

212 ter membrane of mitochondria, interacts with vIRF-1, which, in turn, inhibits MAVS-mediated antiviral

213 The p300 domain, which interacts with vIRF-3, is distinct from the previously identified IBiD

214 Genetic interference with vIRF-1 expression or targeting to the mitochondria inhib

215 ipheral blood mononuclear cells (PBMCs) with vIRF-ko RRV resulted in earlier and increased induction

216 Experimental infection of RMs with vIRF-ko RRV resulted in decreased viral loads and dimini