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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

32 viral homologs of the cellular IRFs, called vIRFs.

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

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

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

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

37 that contain regulatory elements controlling vIRF transcription.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

54 mily of viral interferon regulatory factors (vIRFs).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

95 ranscriptional silencer in the regulation of vIRF gene expression.

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

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

98 egion in the upstream regulatory sequence of vIRF gene.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

113 echanisms behind immunomodulation by the RRV vIRFs during infection.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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