Characterization of a mouse interferon gene locus I. Isolation of a cluster of four α-interferon genes

Kelley, Kevin; Pitha, Paula M.

doi:10.1093/nar/13.3.805

Cited by 77 publications

(29 citation statements)

References 35 publications

(38 reference statements)

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“…In addition, virus infection may produce changes in chromatin structure that affect the expression of endogenous genes that are not required in simpler reporter assays. In this regard, it is noted that the non-IFN-␣4 genes are located within the same chromosomal cluster as the immediate-early IFN-␣4 and IFN-␤ genes (17) and therefore may be affected by their actively transcribed neighbors, a regulatory event that would not be reflected by reporter constructs.…”

Section: Resultsmentioning

confidence: 99%

Phosphorylation-Induced Dimerization of Interferon Regulatory Factor 7 Unmasks DNA Binding and a Bipartite Transactivation Domain

Marié

Smith

Prakash

et al. 2000

Molecular and Cellular Biology

133

151

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Interferon regulatory factor 7 (IRF7) is an interferon (IFN)-inducible transcription factor required for activation of a subset of IFN-␣ genes that are expressed with delayed kinetics following viral infection. IRF7 is synthesized as a latent protein and is posttranslationally modified by protein phosphorylation in infected cells. Phosphorylation required a carboxyl-terminal regulatory domain that controlled the retention of the active protein exclusively in the nucleus, as well as its binding to specific DNA target sequences, multimerization, and ability to induce target gene expression. Transcriptional activation by IRF7 mapped to two distinct regions, both of which were required for full activity, while all functions were masked in latent IRF7 by an autoinhibitory domain mapping to an internal region. A conditionally active form of IRF7 was constructed by fusing IRF7 with the ligand-binding and dimerization domain of estrogen receptor (ER). Hormone-dependent dimerization of chimeric IRF7-ER stimulated DNA binding and transcriptional transactivation of endogenous target genes. These studies demonstrate the regulation of IRF7 activity by phosphorylation-dependent allosteric changes that result in dimerization and that facilitate nuclear retention, derepress transactivation, and allow specific DNA binding.

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Section: Resultsmentioning

confidence: 99%

Phosphorylation-Induced Dimerization of Interferon Regulatory Factor 7 Unmasks DNA Binding and a Bipartite Transactivation Domain

Marié

Smith

Prakash

et al. 2000

Molecular and Cellular Biology

133

151

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“…Type I interferon (IFN) 1 family consists of a single IFN␤ gene and multiple IFN␣ genes that are clustered on mouse chromosome 4 (1) and transcriptionally activated in virus-infected cells. Transcriptional induction of the IFN␣/␤ genes is a rapid biphasic process in most cell types; initial induction of IFN␣4 and -␤ is dependent on the constitutively expressed transcription factor IRF3 and subsequent induction of the other members of the IFN␣ family (IRF7-dependent) is achieved after positive feedback resulting in IRF7 protein production and activation (2,3).…”

mentioning

confidence: 99%

Regulatory Serine Residues Mediate Phosphorylation-dependent and Phosphorylation-independent Activation of Interferon Regulatory Factor 7

Caillaud

Hovanessian

Levy

et al. 2005

Journal of Biological Chemistry

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Interferon regulatory factor (IRF)7 is a key transcription factor required for establishment of antiviral resistance. In response to infection, IRF7 is activated by phosphorylation through the action of the non-canonical IB kinases, IB kinase-⑀ and TANK-binding kinase 1. Activation leads to nuclear retention, DNA binding, and derepression of transactivation ability. Clusters of serine residues located in the carboxyl-terminal regulatory domain of IRF7 are putative targets of virus-activated kinases. However, the exact sites of phosphorylation have not yet been established. Here, we report a comprehensive structure-activity examination of potential IRF7 phosphorylation sites through analysis of mutant proteins in which specific serine residues were altered to alanine or aspartate. Phosphorylation patterns of these mutants were analyzed by two-dimensional gel electrophoresis, and their transcriptional activity was monitored by reporter assays. Essential phosphorylation events were mapped to amino acids 437-438 and a redundant set of sites at either amino acids 429 -431 or 441. IRF7 recovered from infected cells was heterogeneously phosphorylated at these sites, and greater phosphorylation correlated with increased transactivation. Interestingly, a distinct serine cluster conserved in the related protein IRF3 was also essential for IRF7 activation and distal phosphorylation. However, the essential role of this motif did not appear to be fulfilled by phosphorylation. Rather, these serine residues and an adjacent leucine were required for phosphorylation at distal sites and may determine a conformational element required for function.Production of type I interferon in response to a wide variety of bacterial and viral infections is a major component of innate immunity and is essential to host defense against microbial invasion. Type I interferon (IFN) 1 family consists of a single IFN␤ gene and multiple IFN␣ genes that are clustered on mouse chromosome 4 (1) and transcriptionally activated in virus-infected cells. Transcriptional induction of the IFN␣/␤ genes is a rapid biphasic process in most cell types; initial induction of IFN␣4 and -␤ is dependent on the constitutively expressed transcription factor IRF3 and subsequent induction of the other members of the IFN␣ family (IRF7-dependent) is achieved after positive feedback resulting in IRF7 protein production and activation (2, 3).Similar to many signaling pathways, the activating switch for transcription is achieved by phosphorylation of specific transcription factors. Transcription of the IFN␤ gene is controlled by an enhanceosome composed of at least the AP1 transcription factor (c-jun-ATF2), phosphorylated by the c-Jun kinase, NFB, released from its inhibitor IB after phosphorylation-induced degradation through the action of the IB kinase (composed of IKK␣, IKK␤, and IKK␥/NEMO), and IRF3 and IRF7, activated by phosphorylation. The kinases thought responsible for phosphorylating IRF3 and IRF7 have been recently identified as distant members of the IKK family, T...

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“…They are encoded by an intronless multigene family clustered on murine chromosome 4. To this date, 1 IFN-␤ and 13 IFN-␣ genes have been described in the mouse, including one pseudogene (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). Classically, IFN-␣/␤ have been studied for their potent antiviral activity but they also exert various immunoregulatory functions such as regulation of major histocompatibility complex (MHC) class-I antigen expression, interleukin (IL)-12 and IL-15 production, and natural killer cell activation, which shape the adaptive immune response to an invading pathogen (12,13).…”

mentioning

confidence: 99%

Characterization of Interferon-α 13, a Novel Constitutive Murine Interferon-α Subtype

Pesch

Michiels

2003

Journal of Biological Chemistry

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Characterization of a mouse interferon gene locus I. Isolation of a cluster of four α-interferon genes

Cited by 77 publications

References 35 publications

Phosphorylation-Induced Dimerization of Interferon Regulatory Factor 7 Unmasks DNA Binding and a Bipartite Transactivation Domain

Phosphorylation-Induced Dimerization of Interferon Regulatory Factor 7 Unmasks DNA Binding and a Bipartite Transactivation Domain

Regulatory Serine Residues Mediate Phosphorylation-dependent and Phosphorylation-independent Activation of Interferon Regulatory Factor 7

Characterization of Interferon-α 13, a Novel Constitutive Murine Interferon-α Subtype

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