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• W2893224804 abstract "See also: Original Article by Zenke et al. Interferon regulatory factor 1 (IRF1) and signal transducer and activator of transcription 1 (STAT1) are both required for the induction of a subgroup of interferon (IFN)-driven genes. However, it is unknown how the two transcription factors interact to upregulate the expression of immune-regulated genes. In an interesting article published in this issue of Immunology & Cell Biology, Zenke and co-authors reported that IRF1 promotes activation of STAT1 (i.e. tyrosine phosphorylation at residue Y701 and subsequent DNA binding).1 The IRF1 protein was originally identified as a transcriptional activator in innate and adaptive immunity, especially IFN signaling, by binding to positive regulatory domains within the promoter of the human IFNβ gene.2-4 IRF1 belongs to the protein family of nine human interferon regulatory factors (IRF1-9) which display diverse physiological functions including immune regulation, host defense, apoptosis, cell cycle control and oncogenesis. All IRFs share a conserved amino-terminal helix-turn-helix DNA-binding domain with a series of tryptophan-rich pentad repeats that recognizes a GAAA motif, termed IRF element (IRE), located within the promoters of the IFNα and IFNβ gene as well as interferon-stimulated genes (ISGs).5 The less well-conserved carboxyl-terminal regions of the IRFs mediate interactions with additional IRFs via IRF-association domains (IAD) and other transcription factors and cofactors, conferring specific activities upon each IRF family member. It is well established that exposure of cells to cytokines and double-stranded RNA (dsRNA) induces IRF1 expression. Upregulation of the IRF1 gene in response to IFN type I (IFNα and IFNβ) and IFN type II (IFNγ) depends on the binding of STAT1 homodimers to a palindromic DNA sequence known as γ-activated sequence (GAS). Additionally, in IFN type I signaling, heterodimeric STAT1–STAT2 complexes are formed and bind, in association with IRF9 (p48), to a distinct group of target genes harboring the interferon-stimulated response element (ISRE). Besides IRF1, the immunoproteasome subunit LMP2 (low molecular mass polypeptide 2) mediates IFNγ-induced antiviral, antitumor and immunomodulatory responses. LMP2, encoded by a gene located within the major histocompatibility complex class II region, is required for efficient antigen processing and MHC-restricted antigen presentation. In an important paper, Chatterjee-Kishore and colleagues showed that a complex of nonactivated (i.e. unphosphorylated) STAT1 and IRF1 binds to a partially overlapping IRE/GAS element in the bidirectional LMP2/TAP2 promoter and supports the basal transcription of the LMP2 gene.6 Moreover, adenoviral protein E1A inhibits the formation of a transcriptionally active STAT1/IRF1 complex at the LMP2 promoter by occupying domains of STAT1 which interact with IRF1.7 These observations suggest that the recruitment of STAT1 and IRF1 to the LMP2 promoter, irrespective of STAT1 phosphorylation, prepares the cell for an incoming attack by viruses, whereas adenovirus E1A downregulates LMP2 transcription by hindering the formation of this complex. Zenke and co-authors reported that the transcriptional activity of IRF1 is required for enhanced STAT1 activation, as a truncated mutant lacking the carboxy-terminal IAD domain, which is required for transactivation and dimerization, failed to increase STAT1 tyrosine phosphorylation.1 Based on these observations, they concluded that IRF1 is engaged in a positive feedback loop of the IFNγ-induced JAK-STAT signaling pathway, which may have functional consequences in the regulation of immune reactions. However, Zenke and co-authors did not present a mechanistic model in their paper of how IRF1 expression results in increased levels of STAT1 tyrosine phosphorylation. One possible explanation for IRF1-overexpressing cells displaying elevated STAT1 activation is that transcriptionally active IRF1 may directly induce the STAT1 gene itself. We hypothesize that either an IRF1 homodimer or a STAT1/IRF1 heterodimer is recruited to the STAT1 promoter in the absence of cytokine stimulation of cells. Given that the STAT1/IRF1 complex has been identified as the transcriptional activator of the LMP2 gene, IRF1 could possibly drive the constitutive expression of the STAT1 gene by collaborating with unphosphorylated (or, in addition, tyrosine-phosphorylated) STAT1 in a similar manner. In the human STAT1 promoter, there is a 5′-TTTCCATATACATAGAA-′3 sequence at position -44 comprising a consensus and putative second IRE sequence (both marked in italics) and a weak overlapping, downstream GAS element (underlined). This putative regulatory motif has sequence similarity to the well-studied LMP2 promoter, as discussed above (5′-TTTCGCTTTCCCCTAA-′3).6 The STAT1 promoter may recruit monomeric or dimeric IRF1, which could interact with a STAT1 protein bound to the 3′-terminal GAA sequence within this motif. Biochemical data and X-ray structures have revealed that DNA-bound IRF9 interacts via its IAD domain with the coiled-coil domain of STAT2.8, 9 A similar interface may also be formed between the homologous IRF1 and STAT1 proteins. According to our model, the heterodimeric or -trimeric IRF1/STAT1 complex is stabilized through cooperative DNA binding. Figure 1 illustrates a simple model for the proposed functional cooperation between IRF1 and STAT1 at the STAT1 promoter. Three scenarios are depicted: (a) binding of an IRF1/STAT1 heterodimer to the 5′-end and 3′-end of the sequence, (b) formation of an IRF1 homodimer at the 5′-end, and (c) recruitment of a heterotrimeric complex with a core IRF1 molecule interacting with a partner IRF1 and STAT1 protein, respectively. Our assumption that IRF1 is engaged as a direct transcriptional inducer of the STAT1 gene comes from the western blot data presented in the article by Zenke and colleagues. The loading controls for the protein extracts in figures 2a, 5a, 5b and 6a showed increased levels of STAT1 concentrations in cells expressing recombinant or endogenous IRF1 as compared to their corresponding controls. These immunoblotting data suggest that IRF1-mediated upregulation of constitutive STAT1 expression is the cause of the subsequent increase in tyrosine phosphorylation and GAS binding in IRF1-overexpressing cells exposed to low levels of STAT1-activating cytokines. While it is well established that GAS-bound STAT1 homodimers are a strong inducer at the IRF1 promoter, it is tempting to suggest that, vice versa, IRF1-mediated transcription facilitates basal STAT1 expression in a positive amplifier loop. Based on the data presented by Zenke et al., further experiments are necessary to test the clinically relevant hypothesis that IRF1 and STAT1 indeed cooperate at distinct functional levels and, thereby, create a highly effective positive feedback amplifier circuit in their common fight against invading pathogens. We thank Priyanka Menon for discussion. This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) und Nachlass der Frau Lore Grun. The authors declare no conflict of interest." @default.
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• W2893224804 date "2018-09-24" @default.
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• W2893224804 title "Do the two transcription factors form a positive feedback amplifier circuit in their common fight against pathogens?" @default.
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• W2893224804 doi "https://doi.org/10.1111/imcb.12198" @default.
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