Viral IFN-Regulatory Factors Inhibit Activation-Induced Cell Death Via Two Positive Regulatory IFN-Regulatory Factor 1-Dependent Domains in the CD95 Ligand Promoter

Kirchhoff, Sabine; Sebens, Thorsten; Baumann, Sven; Krueger, Andreas; Zawatzky, Rainer; Li‐Weber, Min; Meinl, Edgar; Neipel, Frank; Fleckenstein, Bernhard; Krammer, Peter H.

doi:10.4049/jimmunol.168.3.1226

Cited by 65 publications

(50 citation statements)

References 62 publications

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“…The human inducible nitric oxide synthase (hiNOS), Fas (CD95), and caspase-1 genes encode pro-inflammatory and pro-apoptotic proteins that play essential roles in the innate immune response and the control of cell death. All three are induced by IFN-␥ in STAT1-and IRF-1-dependent fashion (22,26,27). Consistent with its enhancing effect on IRF-1 and STAT1 (Fig.…”

Section: Inhibition Of Mtor Enhances the Induction Of Late Ifn-␥-stimsupporting

confidence: 52%

Inactivation of Mammalian Target of Rapamycin Increases STAT1 Nuclear Content and Transcriptional Activity in α4- and Protein Phosphatase 2A-dependent Fashion

Fielhaber¹,

Han²,

Tan

et al. 2009

Journal of Biological Chemistry

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Target of rapamycin (TOR) is a highly conserved serine/threonine kinase that controls cell growth, primarily via regulation of protein synthesis. In Saccharomyces cerevisiae, TOR can also suppress the transcription of stress response genes by a mechanism involving Tap42, a serine/threonine phosphatase subunit, and the transcription factor Msn2. A physical association between mammalian TOR (mTOR) and the transcription factor signal transducer and activator of transcription-1 (STAT1) was recently identified in human cells, suggesting a similar role for mTOR in the transcription of interferon-␥-stimulated genes. In the current study, we identified a macromolecular protein complex composed of mTOR, STAT1, the Tap42 homologue ␣4, and the protein phosphatase 2A catalytic subunit (PP2Ac). Inactivation of mTOR enhanced its association with STAT1 and increased STAT1 nuclear content in PP2Ac-dependent fashion. Depletion of ␣4, PP2A, or mTOR enhanced the induction of early (i.e. IRF-1) and late (i.e. caspase-1, hiNOS, and Fas) STAT1-dependent genes. The regulation of IRF-1 or caspase-1 by mTOR was independent of other known mTOR effectors p70 S6 kinase and Akt. These results describe a new role for mTOR and ␣4/PP2A in the control of STAT1 nuclear content, and the expression of interferon-␥-sensitive genes involved in immunity and apoptosis.The macrocyclic lactone rapamycin (Sirolimus, Rapamune TM ), as well as its analogues temsirolimus (CCI-779, Torisel TM ) and everolimus (RAD-001, Certican TM ), are approved for immunosuppression after organ transplantation, treatment of renal cell carcinoma, and the prevention of coronary artery in-stent restenosis (1). Their only known target is mammalian target of rapamycin (mTOR), 3 a highly conserved protein that controls cell growth in response to mitogens and changes in cellular metabolism. The effects of mTOR on cell growth involve the phosphorylation of p70 S6 kinase (S6K) and the translation inhibitor 4E-BP1, key regulators of ribosomal biogenesis and the initiation of protein synthesis (2). In contrast to its role in the initiation of translation, the current study focuses on mTOR as a regulator of mammalian gene transcription. Studies in Saccharomyces cerevisiae have revealed possible mechanisms by which mTOR might control mammalian transcription factors. TOR-regulated transcriptional control pathways include ribosomal biogenesis, the nutrient deprivation response, and the stress response (3). TOR stimulates 35 S ribosomal RNA expression and ribosomal biogenesis in nutrientdependent fashion. Inhibition of TOR (e.g. rapamycin or amino acid depletion) reproduces a catabolic response in part by inhibiting rRNA synthesis. In the nutrient deprivation and stress responses, TOR controls the nuclear localization of key transcription factors by mechanisms that require its associated serine/threonine phosphatases (i.e. Pph21, Pph22, or Sit4) and their adaptor, Tap42 (3). Rapamycin blocks phosphorylation of the transcription factor Gln3, as well as its cytosolic scaffolding protein Ure...

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Section: Inhibition Of Mtor Enhances the Induction Of Late Ifn-␥-stimsupporting

confidence: 52%

Inactivation of Mammalian Target of Rapamycin Increases STAT1 Nuclear Content and Transcriptional Activity in α4- and Protein Phosphatase 2A-dependent Fashion

Fielhaber¹,

Han²,

Tan

et al. 2009

Journal of Biological Chemistry

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“…Coimmunoprecipitation studies confirm binding of FADD to caspase-8 (Supplementary Figure S2). Since previous literature (Kirchhoff et al, 2002;Park et al, 2004) and our own studies have suggested involvement of the extrinsic death pathway in IRF-1-induced IRF-1 induces ligand-independent FADD-mediated apoptosis MT Stang et al apoptosis, we expected the involvement of death receptors and ligands. We found, however, that the involvement of FADD and caspase-8 signaling appeared to be independent of classical death-ligands since neutralizing antibodies were ineffective in abrogating IRF-1 induced apoptosis.…”

Section: Discussionmentioning

confidence: 88%

Interferon regulatory factor-1-induced apoptosis mediated by a ligand-independent fas-associated death domain pathway in breast cancer cells

et al. 2007

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Interferon (IFN) regulatory factor-1 (IRF-1) is a transcription factor that has apoptotic anti-tumor activity. In breast cancer cell types, IRF-1 is implicated in mediating apoptosis by both novel and established anti-tumor agents, including the anti-estrogens tamoxifen and faslodex. Here we demonstrate that in MDA468 breast cancer cells, apoptosis by IFN-c is mediated by IRF-1 and IFN-c, and IRF-1-induced apoptosis is caspase-mediated. IRF-1 induction results in cleavage of caspase-8, -3 and -7, and application of caspase inhibitors attenuate activated cleavage products. IRF-1-induced apoptosis involves caspase-8 since apoptosis is significantly decreased by the caspase-8-specific inhibitor IETD, c-FLIP expression and in caspase-8-deficient cancer cells. Furthermore, we demonstrate that IRF-1-induced apoptosis requires fas-associated death domain (FADD) since dominant-negative FADD expressing cells resist IRF-1-induced apoptosis and activated downstream products. Immunofluorescent studies demonstrate perinuclear colocalization of FADD and caspase-8. Despite the known role of FADD in mediating death-ligand induced apoptosis, neutralizing antibodies against classical death receptors do not inhibit IRF-1 induced apoptosis, and no secreted ligand appears to be involved since MDA468 coincubated with IRF-1 transfected cells do not apoptose. Therefore, we demonstrate that IRF-1 induces a ligand-independent FADD/caspase-8-mediated apoptosis in breast cancer cells.

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“…1). vIRF-1, encoded by K9, transforms cells in culture, is tumorigenic in nude mice, and inhibits apoptosis induced by Sendai virus infection, IFN-␣, IFN-␤, TNF-␣, TCR/CD3 cross-linking, and p53 (64,160,174,234,258,293,302,369,456,457). It also blocks programmed cell death mediated by cooperation of the cellular protein GRIM19 with IFN-␤ and retinoic acid (456).…”

Section: Lytic Genes and Kshv Pathogenesismentioning

confidence: 99%

“…However, vIRF-1 has been best characterized for inhibiting the transcriptional programs induced by exogenous IFNs (174,293), specifically by blocking transcriptional activation by the cellular proteins IRF-1 and IRF-3. This is mediated by multiple mechanisms, including direct binding of vIRF to its cellular homologs, competitive binding to the transcriptional coactivator p300, and inhibition of the histone acetyltransferase activity of p300 (64,160,258,292,302,550). vIRF-1 also directly binds p53 to inhibit its phosphorylation and acetylation and blocks its ability to transactivate transcription (369,457).…”

Section: Lytic Genes and Kshv Pathogenesismentioning

confidence: 99%

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Molecular Genetics of Kaposi's Sarcoma-Associated Herpesvirus (Human Herpesvirus 8) Epidemiology and Pathogenesis

Dourmishev

Palmeri

et al. 2003

Microbiol Mol Biol Rev

309

367

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Kaposi's sarcoma had been recognized as unique human cancer for a century before it manifested as an AIDS-defining illness with a suspected infectious etiology. The discovery of Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8, in 1994 by using representational difference analysis, a subtractive method previously employed for cloning differences in human genomic DNA, was a fitting harbinger for the powerful bioinformatic approaches since employed to understand its pathogenesis in KS. Indeed, the discovery of KSHV was rapidly followed by publication of its complete sequence, which revealed that the virus had coopted a wide armamentarium of human genes; in the short time since then, the functions of many of these viral gene variants in cell growth control, signaling apoptosis, angiogenesis, and immunomodulation have been characterized. This critical literature review explores the pathogenic potential of these genes within the framework of current knowledge of the basic herpesvirology of KSHV, including the relationships between viral genotypic variation and the four clinicoepidemiologic forms of Kaposi's sarcoma, current viral detection methods and their utility, primary infection by KSHV, tissue culture and animal models of latent- and lytic-cycle gene expression and pathogenesis, and viral reactivation from latency. Recent advances in models of de novo endothelial infection, microarray analyses of the host response to infection, receptor identification, and cloning of full-length, infectious KSHV genomic DNA promise to reveal key molecular mechanisms of the candidate pathogeneic genes when expressed in the context of viral infection

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Viral IFN-Regulatory Factors Inhibit Activation-Induced Cell Death Via Two Positive Regulatory IFN-Regulatory Factor 1-Dependent Domains in the CD95 Ligand Promoter

Cited by 65 publications

References 62 publications

Inactivation of Mammalian Target of Rapamycin Increases STAT1 Nuclear Content and Transcriptional Activity in α4- and Protein Phosphatase 2A-dependent Fashion

Inactivation of Mammalian Target of Rapamycin Increases STAT1 Nuclear Content and Transcriptional Activity in α4- and Protein Phosphatase 2A-dependent Fashion

Interferon regulatory factor-1-induced apoptosis mediated by a ligand-independent fas-associated death domain pathway in breast cancer cells

Molecular Genetics of Kaposi's Sarcoma-Associated Herpesvirus (Human Herpesvirus 8) Epidemiology and Pathogenesis

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