Differential Regulation of Human Interferon A Gene Expression by Interferon Regulatory Factors 3 and 7

Abstract

Differential expression of the human interferon A (IFN-A) gene cluster is modulated following paramyxovirus infection by the relative amounts of active interferon regulatory factor 3 (IRF-3) and IRF-7. IRF-3 expression activates predominantly IFN-A1 and IFN-B, while IRF-7 expression induces multiple IFN-A genes. [...] Chromatin immunoprecipitation experiments reveal that transient binding of both IRF-3 and IRF-7, accompanied by CBP/p300 recruitment to the endogenous IFN-A gene promoters, is associated with transcriptional activation, whereas a biphasic recruitment of IRF-3 and CBP/p300 represses IFN-A gene expression. This regulatory mechanism contributes to differential expression of IFN-A genes and may be critical for alpha interferon production in different cell types by RIG-I-dependent signals, leading to innate antiviral immune responses

Zebrafish IRF1, IRF3, and IRF7 Differentially Regulate IFNΦ1 and IFNΦ3 Expression through Assembly of Homo- or Heteroprotein Complexes

“…In mammals, IRF3 phosphorylation leads to its homo or heterodimerization, nuclear translocation, and association with b-catenin and CBP/p300, and this is the transcriptional complex for IFNb expression (4,7,51,55). Consistently, fish IRF3 and IRF7 localize in cytoplasm of unstimulated cells (28,44,56), and undergo a cytoplasmic-to-nuclear translocation following poly(I:C) treatment or virus infection, likely through phosphorylation (28,56).…”

“…Similar results are observed in mammals. Human IRF3 selectively binds to distinct IRF-E motifs within IFNa and IFNb gene promoters (51); however, this factor activates the expression of early-phase IFN genes like IFNb but has no effect on most IFNa gene expression (6,7,51). Similar to DrIRF3, human IRF3 selectively exerts a similarly dual effect on IRF7-mediated IFNa gene expression (7) and an inhibitory effect on IRF1-mediated IFNa4 gene expression (5).…”

“…5). In mammals, IRF3 possesses a restricted recognizing DNA sequence, but IRF7 has a broader one (51); this selective binding contributes to differential regulation of early-phase IFN genes, including IFNb, and later-phase IFN genes, including most IFNas: the former is primarily controlled by IRF3, and the latter are controlled by IRF7 (6)(7)(8)(51)(52)(53). Considering that the IRF3/7-dependent IFN response is activated from cytosolic locations in most cell types (8), the similar binding and regulatory properties of DrIRF3 and DrIRF7 support our previous notion that RLR pathway-triggered DrIFNF1 expression is primarily regulated by DrIRF3, thereby resembling mammalian IFNb, and DrIFNF3 is primarily regulated by DrIRF7, thereby resembling mammalian IFNas (29).…”

“…All IRFs contain a conserved N-terminal DNA-binding domain (DBD) characterized by five tryptophan repeat elements. By folding to a helix-turn-helix motif, DBD specifically recognizes and binds to a similar DNA sequence termed an IRF-binding element (IRF-E)/IFN-stimulated response element (ISRE) within the promoters of type I IFN genes and IFN-stimulated genes (4)(5)(6)(7). In addition to DBD, each family member contains a unique C-terminal IRF-associated domain that accounts for interactions with other IRFs and transcription factors (1).…”

A human herpesvirus miRNA attenuates interferon signaling and contributes to maintenance of viral latency by targeting IKKɛ

“…Recently, a model was reported in which a major latent protein, LANA, was able npg to inhibit IFNB expression by competing with IRF3 for binding to the IFNB promoter [32]. Since activation of IFNAs and IFNB are very heterogeneous [33], this proposed model is unlikely to fully explain every molecular scenario.…”