Unknown,Transcriptomics,Genomics,Proteomics

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Transcription Factor Redundancy Ensures Induction of the Antiviral State

ABSTRACT: Transcriptional response to virus infection in mice lacking type I and type III signaling The transcriptional response to virus infection is thought to be predominantly induced by interferon (IFN) signaling. Here we demonstrate that, in the absence of IFN signaling, an IFN-like transcriptome is still maintained. This transcriptional activity is mediated from IFN-stimulated response elements (ISREs) that bind to both the IFN stimulated gene factor 3 (ISGF3) as well as to IFN response factor 7 (IRF7). Through a combination of both in vitro biochemistry and in vivo transcriptional profiling, we have dissected what constitutes IRF-specific, ISGF3-specific, or universal ISREs. Taken together, the data presented here suggests that IRF7 can induce an IFN-like transcriptome in the absence of type-I or -III signaling and therefore provides a level of redundancy to cells to ensure the induction of the antiviral state. Mouse: Infections were performed in triplicate and lungs from each condition were pooled for total RNA isolation. Human: Analysis of IRF7 transcriptome in U3A cell line was performed in duplicates.

ORGANISM(S): Homo sapiens

SUBMITTER: Benjamin tenOever

PROVIDER: E-GEOD-24695 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Transcription factor redundancy ensures induction of the antiviral state.

Schmid Sonja S Mordstein Markus M Kochs Georg G García-Sastre Adolfo A Tenoever Benjamin R BR

The Journal of biological chemistry 20101013 53

The transcriptional response to virus infection is thought to be predominantly induced by interferon (IFN) signaling. Here we demonstrate that, in the absence of IFN signaling, an IFN-like transcriptome is still maintained. This transcriptional activity is mediated from IFN-stimulated response elements (ISREs) that bind to both the IFN-stimulated gene factor 3 (ISGF3) as well as to IFN response factor 7 (IRF7). Through a combination of both in vitro biochemistry and in vivo transcriptional profi ...[more]

PMID: 20943654

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Project description:Type I Interferons (IFN-I) mediate cellular responses to virus infection. IFN-I induce IFN stimulated gene (ISG) expression by phosphorylating STAT1 and STAT2, and together with interferon regulatory factor (IRF)9, form the transcription complex ISGF3 that binds to the interferon-stimulated response element (ISRE) in ISG promoters. As a component of ISGF3 it is clear that STAT2 plays an essential role in the transcriptional responses to IFN-I with a strong dependence on STAT1. Previously, we showed that STAT2 also forms homodimers that interact with IRF9 (STAT2-IRF9) to activate transcription of ISRE containing ISGs in response to IFN-I. Indeed, evidence is accumulating for the existence of a STAT1-independent IFN-I signaling pathway, where STAT2-IRF9 can substitute the role of ISGF3. Here, we provide further insight in the transcriptional regulation and the biological implications of STAT2-IRF9 dependent IFN-I signaling. In human STAT1 KO cells overexpressing human STAT2 (U3C-STAT2) we observed that in response to IFN-I STAT2 homodimers interact with IRF9 to regulate ISG transcription. The IFN-I-induced phosphorylation profile of STAT2 in U3C-STAT2 was prolonged as compared to WT cells (2fTGH), which corresponded with the expression pattern of OAS2 that also depended on IRF9. Subsequent microarray analysis of IFN-I treated 2fTGH and U3C-STAT2 extended our initial observations and identified more than 60 known antiviral ISGs commonly up-regulated in both cell types. The expression profile of these ISGs was delayed and prolonged in U3C-STAT2 as opposed to the early and transient response in 2fTGH. Moreover, U3C-STAT2 were able to restore an antiviral response upon EMCV and VSV infection that was comparable to the response in 2fTGH. Together, our results strongly suggest that an alternative IFN-I-mediated, STAT2-IRF9 dependent signaling pathway exists that can generate an antiviral response without STAT1 and could be beneficial for example against viruses that directly block STAT1 and impair the formation of ISGF3.

Project description:Type I Interferons (IFN-I) mediate cellular responses to virus infection. IFN-I induces IFN-stimulated gene (ISG) expression by phosphorylating STAT1 and STAT2, and together with interferon regulatory factor (IRF9), form the transcription complex ISGF3 that binds to the interferon-stimulated response element (ISRE) in ISG promoters. As a component of ISGF3, it is clear that STAT2 plays an essential role in the transcriptional responses to IFN-I with a strong dependence on STAT1. Previously, we showed that STAT2 also forms homodimers that interact with IRF9 (STAT2-IRF9) to activate transcription of ISRE-containing ISGs in response to IFN-I. Indeed, evidence is accumulating for the existence of a STAT1-independent IFN-I signaling pathway, where STAT2-IRF9 can substitute the role of ISGF3. Here, we provide further insight in the transcriptional regulation and the biological implications of STAT2-IRF9 dependent IFN-I signaling. In human STAT1 KO cells overexpressing human STAT2 (U3C-STAT2), we observed that in response to IFN-I, STAT2 homodimers interact with IRF9 to regulate ISG transcription. The IFN-I-induced phosphorylation profile of STAT2 in U3C-STAT2 was prolonged as compared to WT cells (2fTGH), which corresponded with the expression pattern of OAS2 that also depended on IRF9. Subsequent microarray analysis of IFN-I treated 2fTGH and U3C-STAT2 extended our initial observations and identified more than 60 known antiviral ISGs commonly up-regulated in both cell types. The expression profile of these ISGs was delayed and prolonged in U3C-STAT2 as opposed to the early and transient response in 2fTGH. Moreover, U3C-STAT2 were able to restore an antiviral response upon EMCV and VSV infection that was comparable to the response in 2fTGH. Together, our results strongly suggest that an alternative IFN-I-mediated, STAT2-IRF9 dependent signaling pathway exists that can generate an antiviral response without STAT1 and could be beneficial for example against viruses that directly block STAT1 and impair the formation of ISGF3.

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Transcription Factor Redundancy Ensures Induction of the Antiviral State

Publications

Transcription factor redundancy ensures induction of the antiviral state.

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