IFNβ-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage

Cheon, HyeonJoo; Holvey-Bates, Elise; Schoggins, John W.; Forster, Samuel C.; Hertzog, Paul J.; Imanaka, Naoko; Rice, Charles M.; Jackson, Mark W.; Junk, Damian J.; Stark, George R.

doi:10.1038/emboj.2013.203

Cited by 297 publications

(362 citation statements)

References 51 publications

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“…After incubation with Alexa goat anti-rabbit Ab, cells were washed and counterstained with 4=,6-diamidino-2-phenylindole (DAPI). The cells were visualized with a Zeiss fluorescence LSM510 confocal microscope at ϫ63 magnification (43,76). Fluorescence intensity was quantified in 5 independent fields using ImageJ.…”

Section: Methodsmentioning

confidence: 99%

“…Human IRF1 and IRF7 cDNAs (plasmid templates were kindly provided by Charles M. Rice [74] and Fanxiu Zhu [75], respectively) were cloned into the lentiviral vector pLV-tetO-CMV-SV40-Puro-LoxP (kindly provided by George R. Stark [76]). To produce infectious lentiviruses, each construct was transfected into 293FT packaging cells using Lipofectamine 2000 (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

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BRD4 Couples NF-κB/RelA with Airway Inflammation and the IRF-RIG-I Amplification Loop in Respiratory Syncytial Virus Infection

Tian

Yang

Zhao

et al. 2017

J Virol

138

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The airway mucosa expresses protective interferon (IFN) and inflammatory cytokines in response to respiratory syncytial virus (RSV) infection. In this study, we examine the role of bromodomain containing 4 (BRD4) in mediating this innate immune response in human small airway epithelial cells. We observe that RSV induces BRD4 to complex with NF-B/RelA. BRD4 is functionally required for expression of the NF-Bdependent inflammatory gene regulatory network (GRN), including the IFN response factor 1 (IRF1) and IRF7, which mediate a cross talk pathway for RIG-I upregulation. Mechanistically, BRD4 is required for cyclin-dependent kinase 9 (CDK9) recruitment and phospho-Ser 2 carboxy-terminal domain (CTD) RNA polymerase (Pol) II formation on the promoters of IRF1, IRF7, and RIG-I, producing their enhanced expression by transcriptional elongation. We also find that BRD4 independently regulates CDK9/ phospho-Ser 2 CTD RNA Pol II recruitment to the IRF3-dependent IFN-stimulated genes (ISGs). In vivo, poly(I·C)-induced neutrophilia and mucosal chemokine production are blocked by a small-molecule BRD4 bromodomain inhibitor. Similarly, BRD4 inhibition reduces RSV-induced neutrophilia, mucosal CXC chemokine expression, activation of the IRF7-RIG-I autoamplification loop, mucosal IFN expression, and airway obstruction. RSV infection activates BRD4 acetyltransferase activity on histone H3 Lys (K) 122, demonstrating that RSV infection activates BRD4 in vivo. These data validate BRD4 as a major effector of RSV-induced inflammation and disease. BRD4 is required for coupling NF-B to expression of inflammatory genes and the IRF-RIG-I autoamplification pathway and independently facilitates antiviral ISG expression. BRD4 inhibition may be a strategy to reduce exuberant virus-induced mucosal airway inflammation. IMPORTANCEIn the United States, 2.1 million children annually require medical attention for RSV infections. A first line of defense is the expression of the innate gene network by infected epithelial cells. Expression of the innate response requires the recruitment of transcriptional elongation factors to rapidly induce innate response genes through an unknown mechanism. We discovered that RSV infection induces a complex of bromodomain containing 4 (BRD4) with NF-B and cyclindependent kinase 9 (CDK9). BRD4 is required for stable CDK9 binding, phosphoSer 2 RNA Pol II formation, and histone acetyltransferase activity. Inhibition of BRD4 blocks Toll-like receptor 3 (TLR3)-dependent neutrophilia and RSV-induced inflammation, demonstrating its importance in the mucosal innate response in vivo. Our study shows that BRD4 plays a central role in inflammation and activation of the IRF7-RIG-I amplification loop vital for mucosal interferon expression. BRD4 inhibition may be a strategy for modulating exuberant mucosal airway inflammation.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

BRD4 Couples NF-κB/RelA with Airway Inflammation and the IRF-RIG-I Amplification Loop in Respiratory Syncytial Virus Infection

Tian

Yang

Zhao

et al. 2017

J Virol

138

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“…Stat1 function in cell survival as well as cell death may be explained by its ability to respond to drugs via pathways that are controlled by its phosphorylation in a temporal fashion. For example, phosphorylated Stat1 may be initially required to increase cell sensitivity to drugs, whereas de/unphosphorylated Stat1 acts at a later stage to contribute to survival and development of drug resistance (2,62).…”

Section: Stat1 Protects Cells From the Antiproliferative Effects Of Amentioning

confidence: 99%

“…Stat1 Y701 phosphorylation is crucial for DNA binding and transcriptional function, whereas serine (S) 727 phosphorylation promotes gene transactivation in response to IFNs (1). Nevertheless, unphosphorylated Stat1 also possesses transcriptional functions in cells infected with viruses or exposed to DNA damage (1)(2)(3).…”

mentioning

confidence: 99%

Stat1 stimulates cap-independent mRNA translation to inhibit cell proliferation and promote survival in response to antitumor drugs

Wang

Patsis

Koromilas

2015

Proc. Natl. Acad. Sci. U.S.A.

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The signal transducer and activator of transcription 1 (Stat1) functions as a tumor suppressor via immune regulatory and cell-autonomous pathways. Herein, we report a previously unidentified cell-autonomous Stat1 function, which is its ability to exhibit both antiproliferative and prosurvival properties by facilitating translation of mRNAs encoding for the cyclin-dependent kinase inhibitor p27Kip1 and antiapoptotic proteins X-linked inhibitor of apoptosis and B-cell lymphoma xl. Translation of the select mRNAs requires the transcriptional function of Stat1, resulting in the up-regulation of the p110γ subunit of phosphoinositide 3-kinase (PI3K) class IB and increased expression of the translational repressor translation initiation factor 4E (eIF4E)-binding protein 1 (4EBP1). Increased PI3Kγ signaling promotes the degradation of the eIF4A inhibitor programmed cell death protein 4, which favors the cap-independent translation of the select mRNAs under conditions of general inhibition of protein synthesis by up-regulated eIF4E-binding protein 1. As such, Stat1 inhibits cell proliferation but also renders cells increasingly resistant to antiproliferative effects of pharmacological inhibitors of PI3K and/or mammalian target of rapamycin. Stat1 also protects Ras-transformed cells from the genotoxic effects of doxorubicin in culture and immune-deficient mice. Our findings demonstrate an important role of mRNA translation in the cell-autonomous Stat1 functions, with implications in tumor growth and treatment with chemotherapeutic drugs.

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“…Recently, enhanced levels of constitutively expressed ISGs have been reported in advanced cancers and were often associated with a poor prognosis related to aggressive tumor growth, metastatic spread, resistance to IR/chemotherapy, or combinations of these factors (11)(12)(13)(14)(15)(16)(17)(18). The studies presented in this report are based on the hypothesis that a specific set of constitutively expressed ISGs, whose enhanced expression is by cytotoxic stress, confers a selective advantage to individual tumor clones (5,9,10,13,19).…”

mentioning

confidence: 99%

RIG-I–like receptor LGP2 protects tumor cells from ionizing radiation

Widau¹,

Parekh²,

Ranck³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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An siRNA screen targeting 89 IFN stimulated genes in 14 different cancer cell lines pointed to the RIG-I (retinoic acid inducible gene I)-like receptor Laboratory of Genetics and Physiology 2 (LGP2) as playing a key role in conferring tumor cell survival following cytotoxic stress induced by ionizing radiation (IR). Studies on the role of LGP2 revealed the following: (i) Depletion of LGP2 in three cancer cell lines resulted in a significant increase in cell death following IR, (ii) ectopic expression of LGP2 in cells increased resistance to IR, and (iii) IR enhanced LGP2 expression in three cell lines tested. Studies designed to define the mechanism by which LGP2 acts point to its role in regulation of IFNβ. Specifically (i) suppression of LGP2 leads to enhanced IFNβ, (ii) cytotoxic effects following IR correlated with expression of IFNβ inasmuch as inhibition of IFNβ by neutralizing antibody conferred resistance to cell death, and (iii) mouse embryonic fibroblasts from IFN receptor 1 knockout mice are radioresistant compared with wild-type mouse embryonic fibroblasts. The role of LGP2 in cancer may be inferred from cumulative data showing elevated levels of LGP2 in cancer cells are associated with more adverse clinical outcomes. Our results indicate that cytotoxic stress exemplified by IR induces IFNβ and enhances the expression of LGP2. Enhanced expression of LGP2 suppresses the IFN stimulated genes associated with cytotoxic stress by turning off the expression of IFNβ.innate immunity | cytoplasmic sensor | interferon beta | DHX58

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IFNβ-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage

Cited by 297 publications

References 51 publications

BRD4 Couples NF-κB/RelA with Airway Inflammation and the IRF-RIG-I Amplification Loop in Respiratory Syncytial Virus Infection

BRD4 Couples NF-κB/RelA with Airway Inflammation and the IRF-RIG-I Amplification Loop in Respiratory Syncytial Virus Infection

Stat1 stimulates cap-independent mRNA translation to inhibit cell proliferation and promote survival in response to antitumor drugs

RIG-I–like receptor LGP2 protects tumor cells from ionizing radiation

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