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The transcription factor MafB antagonizes antiviral responses by blocking recruitment of coactivators to the transcription factor IRF3.

Kim H, Seed B - Nat. Immunol. (2010)

Bottom Line: MafB acted as a weak positive basal regulator of transcription at the IFNB1 promoter through activity at transcription factor AP-1-like sites.Interferon elicitors recruited the transcription factor IRF3 to the promoter, whereupon MafB acted as a transcriptional antagonist, impairing the interaction of coactivators with IRF3.Mathematical modeling supported the view that prepositioning of MafB on the promoter allows the system to respond rapidly to fluctuations in IRF3 activity.

View Article: PubMed Central - PubMed

Affiliation: Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.

ABSTRACT
Viral infection induces type I interferons (IFN-alpha and IFN-beta) that recruit unexposed cells in a self-amplifying response. We report that the transcription factor MafB thwarts auto-amplification by a metastable switch activity. MafB acted as a weak positive basal regulator of transcription at the IFNB1 promoter through activity at transcription factor AP-1-like sites. Interferon elicitors recruited the transcription factor IRF3 to the promoter, whereupon MafB acted as a transcriptional antagonist, impairing the interaction of coactivators with IRF3. Mathematical modeling supported the view that prepositioning of MafB on the promoter allows the system to respond rapidly to fluctuations in IRF3 activity. Higher expression of MafB in human pancreatic islet beta cells might increase cellular vulnerability to viral infections associated with the etiology of type 1 diabetes.

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Regulation of MAFB expression in response to pathogen triggers. (a) The levels of MAFB and c-MAF mRNAs in 293ETN cells were measured by RT-PCR at the indicated times after poly(I:C) induction. Values were normalized to β-actin expression, and further normalized to the corresponding value before poly(I:C) induction. (b–e), Regulatory patterns of expression of MAFB and other large MAF transcription factors in response to pathogen-mimetic stimulation in a variety of cell types. (b) Human monocyte-derived dendritic cells in response to LPS or the synthetic imidazoquinoline resiquimod R84827, a TLR7/8 agonist, (c) murine bone marrow-derived dendritic cells in response to lipid-transfected double-stranded DNA (dsDNA) or CpG oligonucleotides28, a TLR9 agonist, (d) murine plasmacytoid dendritic cells (pDC) in response to CpG oligonucleotides31, and (e) human pancreatic islet cells in response to coxsackievirus32. Microarray expression values were standardized (to Z-values) for each probe set separately, and data are expressed as mean ± SD of each treatment for each indicated probe (x-axis). (f) Expression patterns of MAFB in naïve and HCV-replicon-containing (Clone A) Huh7 cells. Microarray expression values (measured in triplicate)33 were normalized to the values of naïve Huh7.
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Figure 5: Regulation of MAFB expression in response to pathogen triggers. (a) The levels of MAFB and c-MAF mRNAs in 293ETN cells were measured by RT-PCR at the indicated times after poly(I:C) induction. Values were normalized to β-actin expression, and further normalized to the corresponding value before poly(I:C) induction. (b–e), Regulatory patterns of expression of MAFB and other large MAF transcription factors in response to pathogen-mimetic stimulation in a variety of cell types. (b) Human monocyte-derived dendritic cells in response to LPS or the synthetic imidazoquinoline resiquimod R84827, a TLR7/8 agonist, (c) murine bone marrow-derived dendritic cells in response to lipid-transfected double-stranded DNA (dsDNA) or CpG oligonucleotides28, a TLR9 agonist, (d) murine plasmacytoid dendritic cells (pDC) in response to CpG oligonucleotides31, and (e) human pancreatic islet cells in response to coxsackievirus32. Microarray expression values were standardized (to Z-values) for each probe set separately, and data are expressed as mean ± SD of each treatment for each indicated probe (x-axis). (f) Expression patterns of MAFB in naïve and HCV-replicon-containing (Clone A) Huh7 cells. Microarray expression values (measured in triplicate)33 were normalized to the values of naïve Huh7.

Mentions: We next investigated how the expression of MAFB varies in response to a viral trigger. MAFB expression in 293ETN cells decreased upon poly(I:C) stimulation (Fig. 5a) and the expression of MAFB over time was inversely correlated with that of IFN-α and β (Fig. 1d and e). Expression of c-MAF, another member of the large MAF family protein, also declined in 293ETN cells (Fig. 5a) in response to poly(I:C) stimulation, and c-MAF suppressed IFN-β activation triggered by a range of Type I IFN inducers including poly(I:C), RIG-I(N) and MDA5(N) (Supplementary Fig. 8a). Expression of the large MAF transcription factors, MAFA and NRL, was modest compared to MAFB and c-MAF in 293ETN cells (data not shown). The change in MAFB abundance differs from that of other reported negative regulators of Type I IFN signaling pathway2, such as A20, DUBA and RNF125, the expression of which is upregulated by viral triggers. Attenuation of MAFB expression upon induction suggests that MAFB acts principally to restrain Type I IFN production in response to low-level cues that might not reflect actual viral infections.


The transcription factor MafB antagonizes antiviral responses by blocking recruitment of coactivators to the transcription factor IRF3.

Kim H, Seed B - Nat. Immunol. (2010)

Regulation of MAFB expression in response to pathogen triggers. (a) The levels of MAFB and c-MAF mRNAs in 293ETN cells were measured by RT-PCR at the indicated times after poly(I:C) induction. Values were normalized to β-actin expression, and further normalized to the corresponding value before poly(I:C) induction. (b–e), Regulatory patterns of expression of MAFB and other large MAF transcription factors in response to pathogen-mimetic stimulation in a variety of cell types. (b) Human monocyte-derived dendritic cells in response to LPS or the synthetic imidazoquinoline resiquimod R84827, a TLR7/8 agonist, (c) murine bone marrow-derived dendritic cells in response to lipid-transfected double-stranded DNA (dsDNA) or CpG oligonucleotides28, a TLR9 agonist, (d) murine plasmacytoid dendritic cells (pDC) in response to CpG oligonucleotides31, and (e) human pancreatic islet cells in response to coxsackievirus32. Microarray expression values were standardized (to Z-values) for each probe set separately, and data are expressed as mean ± SD of each treatment for each indicated probe (x-axis). (f) Expression patterns of MAFB in naïve and HCV-replicon-containing (Clone A) Huh7 cells. Microarray expression values (measured in triplicate)33 were normalized to the values of naïve Huh7.
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Figure 5: Regulation of MAFB expression in response to pathogen triggers. (a) The levels of MAFB and c-MAF mRNAs in 293ETN cells were measured by RT-PCR at the indicated times after poly(I:C) induction. Values were normalized to β-actin expression, and further normalized to the corresponding value before poly(I:C) induction. (b–e), Regulatory patterns of expression of MAFB and other large MAF transcription factors in response to pathogen-mimetic stimulation in a variety of cell types. (b) Human monocyte-derived dendritic cells in response to LPS or the synthetic imidazoquinoline resiquimod R84827, a TLR7/8 agonist, (c) murine bone marrow-derived dendritic cells in response to lipid-transfected double-stranded DNA (dsDNA) or CpG oligonucleotides28, a TLR9 agonist, (d) murine plasmacytoid dendritic cells (pDC) in response to CpG oligonucleotides31, and (e) human pancreatic islet cells in response to coxsackievirus32. Microarray expression values were standardized (to Z-values) for each probe set separately, and data are expressed as mean ± SD of each treatment for each indicated probe (x-axis). (f) Expression patterns of MAFB in naïve and HCV-replicon-containing (Clone A) Huh7 cells. Microarray expression values (measured in triplicate)33 were normalized to the values of naïve Huh7.
Mentions: We next investigated how the expression of MAFB varies in response to a viral trigger. MAFB expression in 293ETN cells decreased upon poly(I:C) stimulation (Fig. 5a) and the expression of MAFB over time was inversely correlated with that of IFN-α and β (Fig. 1d and e). Expression of c-MAF, another member of the large MAF family protein, also declined in 293ETN cells (Fig. 5a) in response to poly(I:C) stimulation, and c-MAF suppressed IFN-β activation triggered by a range of Type I IFN inducers including poly(I:C), RIG-I(N) and MDA5(N) (Supplementary Fig. 8a). Expression of the large MAF transcription factors, MAFA and NRL, was modest compared to MAFB and c-MAF in 293ETN cells (data not shown). The change in MAFB abundance differs from that of other reported negative regulators of Type I IFN signaling pathway2, such as A20, DUBA and RNF125, the expression of which is upregulated by viral triggers. Attenuation of MAFB expression upon induction suggests that MAFB acts principally to restrain Type I IFN production in response to low-level cues that might not reflect actual viral infections.

Bottom Line: MafB acted as a weak positive basal regulator of transcription at the IFNB1 promoter through activity at transcription factor AP-1-like sites.Interferon elicitors recruited the transcription factor IRF3 to the promoter, whereupon MafB acted as a transcriptional antagonist, impairing the interaction of coactivators with IRF3.Mathematical modeling supported the view that prepositioning of MafB on the promoter allows the system to respond rapidly to fluctuations in IRF3 activity.

View Article: PubMed Central - PubMed

Affiliation: Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.

ABSTRACT
Viral infection induces type I interferons (IFN-alpha and IFN-beta) that recruit unexposed cells in a self-amplifying response. We report that the transcription factor MafB thwarts auto-amplification by a metastable switch activity. MafB acted as a weak positive basal regulator of transcription at the IFNB1 promoter through activity at transcription factor AP-1-like sites. Interferon elicitors recruited the transcription factor IRF3 to the promoter, whereupon MafB acted as a transcriptional antagonist, impairing the interaction of coactivators with IRF3. Mathematical modeling supported the view that prepositioning of MafB on the promoter allows the system to respond rapidly to fluctuations in IRF3 activity. Higher expression of MafB in human pancreatic islet beta cells might increase cellular vulnerability to viral infections associated with the etiology of type 1 diabetes.

Show MeSH
Related in: MedlinePlus