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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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Roles of MAFB in pancreatic β cells. (a, b). Microarray-based expression patterns of MAFB in human pancreatic tissues. (a) Islet versus exocrine pancreas37 and (b) Purified β cells versus total islet cells38. For each microarray platform, MAFB expression values were normalized to the value of (a) exocrine pancreas and (b) total islet cells. Data indicate (a) mean ± SD (for pancreatic tissues) and a single pooled value (for kidney and liver) of at least two donors, and (b) mean ± SD of three donors. (c, d), Effect of human MAFB overexpression on (c) mIFN-β-Luc activation and (d) VSV replication in a murine β cell line. MIN6 cells transfected with empty control or MAFB were (c) cotransfected with mIFN-β-Luc together with RIG-I(N) or MDA5(N) at 0 h or (d) infected with VSV-Luc 24 h later. Luciferase activities were measured at 34 h post-transfection. (e, f) Age-dependent changes in Mafb expression in islet tissue of NOD mice. (e) beta cell-rich core of islets collected using LCM and (f) whole islets isolated by collagenase perfusion. Mafb and Emr1 mRNA levels were measured by RT-PCR at the age indicated. (e) The blood glucose level for each mouse (mg/dl) is shown in parenthesis. (f) For each age group, two mice were used to obtain pooled total RNA (with blood glucose (mg/dl) of 115 and 143 for 10-week-old and 550 and 579 for 14-week-old). Values were normalized to GAPDH expression, and further normalized to the corresponding values from the youngest mouse (group).
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Figure 6: Roles of MAFB in pancreatic β cells. (a, b). Microarray-based expression patterns of MAFB in human pancreatic tissues. (a) Islet versus exocrine pancreas37 and (b) Purified β cells versus total islet cells38. For each microarray platform, MAFB expression values were normalized to the value of (a) exocrine pancreas and (b) total islet cells. Data indicate (a) mean ± SD (for pancreatic tissues) and a single pooled value (for kidney and liver) of at least two donors, and (b) mean ± SD of three donors. (c, d), Effect of human MAFB overexpression on (c) mIFN-β-Luc activation and (d) VSV replication in a murine β cell line. MIN6 cells transfected with empty control or MAFB were (c) cotransfected with mIFN-β-Luc together with RIG-I(N) or MDA5(N) at 0 h or (d) infected with VSV-Luc 24 h later. Luciferase activities were measured at 34 h post-transfection. (e, f) Age-dependent changes in Mafb expression in islet tissue of NOD mice. (e) beta cell-rich core of islets collected using LCM and (f) whole islets isolated by collagenase perfusion. Mafb and Emr1 mRNA levels were measured by RT-PCR at the age indicated. (e) The blood glucose level for each mouse (mg/dl) is shown in parenthesis. (f) For each age group, two mice were used to obtain pooled total RNA (with blood glucose (mg/dl) of 115 and 143 for 10-week-old and 550 and 579 for 14-week-old). Values were normalized to GAPDH expression, and further normalized to the corresponding values from the youngest mouse (group).

Mentions: The finding that MAFB expression might predispose cells to viral infection suggests that cells highly expressing MAFB could be vulnerable to viruses. For example, Enteroviruses such as coxsackievirus are capable of infecting pancreatic tissues and such infection might be a trigger for the development of type I diabetes (T1D)34,35. Enterovirus infection is specific to endocrine pancreatic islet cells, but not to exocrine pancreas, in humans35,36. The known enterovirus tropism shows a good correlation with the pancreatic expression pattern of MAFB in humans (Fig. 6a)37. Further, MAFB expression is higher in purified human β cells (Fig. 6b)38, which constitute over 60% of the islet population32, than in islets themselves, suggesting that in humans MAFB expression is maintained at a relatively high level in mature β cells. By contrast, in mice, enterovirus infection of healthy islets is limited even in lethal cases35,39, consistent with the relatively low level of Mafb expression in adult mouse islets7. Mafb expression is restricted to α cells in the adult mouse although the expression is observed both in α and β cells in the mouse embryo. To examine whether the differential MAFB expression might play a role in the observed cell tropism and species selectivity of enterovirus infection, human MAFB was ectopically expressed in a murine pancreatic β cell line, MIN6, and cellular antiviral responses were monitored. Coexpressed MAFB strongly inhibited activation of the murine Ifn-β promoter triggered by RIG-I(N) and MDA5(N) (Fig. 6c). In addition, MAFB expression considerably enhanced replication of VSV-Luc compared to a mock-transfected control (Fig. 6d). Because Type I interferon might play an essential role in preventing β cell destruction induced by coxsackievirus infection40, it is possible that elevated MAFB expression in human islet cells might predispose these cells to coxsackievirus infection or persistence, thereby increasing susceptibility to type I diabetes. Mafb is a candidate gene within a T1D susceptibility locus, Idd13, in non-obese diabetic (NOD)/Lt mice41.


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

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

Roles of MAFB in pancreatic β cells. (a, b). Microarray-based expression patterns of MAFB in human pancreatic tissues. (a) Islet versus exocrine pancreas37 and (b) Purified β cells versus total islet cells38. For each microarray platform, MAFB expression values were normalized to the value of (a) exocrine pancreas and (b) total islet cells. Data indicate (a) mean ± SD (for pancreatic tissues) and a single pooled value (for kidney and liver) of at least two donors, and (b) mean ± SD of three donors. (c, d), Effect of human MAFB overexpression on (c) mIFN-β-Luc activation and (d) VSV replication in a murine β cell line. MIN6 cells transfected with empty control or MAFB were (c) cotransfected with mIFN-β-Luc together with RIG-I(N) or MDA5(N) at 0 h or (d) infected with VSV-Luc 24 h later. Luciferase activities were measured at 34 h post-transfection. (e, f) Age-dependent changes in Mafb expression in islet tissue of NOD mice. (e) beta cell-rich core of islets collected using LCM and (f) whole islets isolated by collagenase perfusion. Mafb and Emr1 mRNA levels were measured by RT-PCR at the age indicated. (e) The blood glucose level for each mouse (mg/dl) is shown in parenthesis. (f) For each age group, two mice were used to obtain pooled total RNA (with blood glucose (mg/dl) of 115 and 143 for 10-week-old and 550 and 579 for 14-week-old). Values were normalized to GAPDH expression, and further normalized to the corresponding values from the youngest mouse (group).
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Figure 6: Roles of MAFB in pancreatic β cells. (a, b). Microarray-based expression patterns of MAFB in human pancreatic tissues. (a) Islet versus exocrine pancreas37 and (b) Purified β cells versus total islet cells38. For each microarray platform, MAFB expression values were normalized to the value of (a) exocrine pancreas and (b) total islet cells. Data indicate (a) mean ± SD (for pancreatic tissues) and a single pooled value (for kidney and liver) of at least two donors, and (b) mean ± SD of three donors. (c, d), Effect of human MAFB overexpression on (c) mIFN-β-Luc activation and (d) VSV replication in a murine β cell line. MIN6 cells transfected with empty control or MAFB were (c) cotransfected with mIFN-β-Luc together with RIG-I(N) or MDA5(N) at 0 h or (d) infected with VSV-Luc 24 h later. Luciferase activities were measured at 34 h post-transfection. (e, f) Age-dependent changes in Mafb expression in islet tissue of NOD mice. (e) beta cell-rich core of islets collected using LCM and (f) whole islets isolated by collagenase perfusion. Mafb and Emr1 mRNA levels were measured by RT-PCR at the age indicated. (e) The blood glucose level for each mouse (mg/dl) is shown in parenthesis. (f) For each age group, two mice were used to obtain pooled total RNA (with blood glucose (mg/dl) of 115 and 143 for 10-week-old and 550 and 579 for 14-week-old). Values were normalized to GAPDH expression, and further normalized to the corresponding values from the youngest mouse (group).
Mentions: The finding that MAFB expression might predispose cells to viral infection suggests that cells highly expressing MAFB could be vulnerable to viruses. For example, Enteroviruses such as coxsackievirus are capable of infecting pancreatic tissues and such infection might be a trigger for the development of type I diabetes (T1D)34,35. Enterovirus infection is specific to endocrine pancreatic islet cells, but not to exocrine pancreas, in humans35,36. The known enterovirus tropism shows a good correlation with the pancreatic expression pattern of MAFB in humans (Fig. 6a)37. Further, MAFB expression is higher in purified human β cells (Fig. 6b)38, which constitute over 60% of the islet population32, than in islets themselves, suggesting that in humans MAFB expression is maintained at a relatively high level in mature β cells. By contrast, in mice, enterovirus infection of healthy islets is limited even in lethal cases35,39, consistent with the relatively low level of Mafb expression in adult mouse islets7. Mafb expression is restricted to α cells in the adult mouse although the expression is observed both in α and β cells in the mouse embryo. To examine whether the differential MAFB expression might play a role in the observed cell tropism and species selectivity of enterovirus infection, human MAFB was ectopically expressed in a murine pancreatic β cell line, MIN6, and cellular antiviral responses were monitored. Coexpressed MAFB strongly inhibited activation of the murine Ifn-β promoter triggered by RIG-I(N) and MDA5(N) (Fig. 6c). In addition, MAFB expression considerably enhanced replication of VSV-Luc compared to a mock-transfected control (Fig. 6d). Because Type I interferon might play an essential role in preventing β cell destruction induced by coxsackievirus infection40, it is possible that elevated MAFB expression in human islet cells might predispose these cells to coxsackievirus infection or persistence, thereby increasing susceptibility to type I diabetes. Mafb is a candidate gene within a T1D susceptibility locus, Idd13, in non-obese diabetic (NOD)/Lt mice41.

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