Bipartite Nuclear Localization Signal Controls Nuclear Import and DNA-Binding Activity of IFN Regulatory Factor 3

Zhu, Mingzhu; Fang, Ting; Li, Shun; Meng, Kun; Guo, Deyin

doi:10.4049/jimmunol.1500232

Cited by 43 publications

(44 citation statements)

References 42 publications

(40 reference statements)

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“…4). Note that a small amount of IRF3 was detected in nuclei of unstimulated cells, probably reflecting IRF3 shuttling between the cytoplasm and nucleus (47). Interestingly, a similar trend was observed when cells expressed wild-type cFLIP L : there were no visual differences in nuclearly localized IRF3 in unstimulated versus stimulated cells.…”

Section: Resultsmentioning

confidence: 99%

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cFLIPL Interrupts IRF3–CBP–DNA Interactions To Inhibit IRF3-Driven Transcription

Gates

Shisler

2016

The Journal of Immunology

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Type I interferon (IFN) induction is critical for anti-viral and anti-cancer defenses. Proper down-regulation of type I IFN is equally important to avoid deleterious imbalances in the immune response. The cellular FLIP long isoform protein (cFLIPL) controls type I IFN production, but opposing publications show it as either an inhibitor or inducer of type I IFN synthesis. Regardless, the mechanistic basis for cFLIPL regulation is unknown. Because cFLIPL is important in immune cell development and proliferation, and is a target for cancer therapies, it is important to identify how cFLIPL regulates type I IFN production. Data here show that cFLIPL inhibits IRF3, a transcription factor central for IFNβ and ISG expression. This inhibition occurs during virus infection, cellular exposure to poly I:C or TBK1 over-expression. This inhibition is independent of capase-8 activity. cFLIPL binds to IRF3 and disrupts IRF3 interaction with its IFNβ promoter and its co-activator protein (CBP). Mutational analyses reveal that cFLIPL nuclear localization is necessary and sufficient for inhibitory function. This suggests that nuclear cFLIPL prevents IRF3 enhanceosome formation. Unlike other cellular IRF3 inhibitors, cFLIPL did not degrade or dephosphorylate IRF3. Thus, cFLIPL represents a different cellular strategy to inhibit type I IFN production. This new cFLIPL function must be considered to accurately understand how cFLIPL affects immune system development and regulation.

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Section: Resultsmentioning

confidence: 99%

“…This is currently under investigation in our lab. IRF3 is shuttled from the nucleus to the cytoplasm due to the presence of NLSs and NESs (47). Here, we find that cFLIP L inhibits the action of a dimerized phospho-mimetic form of IRF3 (IRF3CA) (Fig.…”

Section: Discussionmentioning

confidence: 99%

cFLIPL Interrupts IRF3–CBP–DNA Interactions To Inhibit IRF3-Driven Transcription

Gates

Shisler

2016

The Journal of Immunology

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“…IRF3 is an important transcription factor in cells. Its regulation of cell functions depends on the nuclear import level of this protein [35]. In this study, we found that the expression and secretion of the cytokine IFN-β was decreased with the down-regulation of the IRF3 protein level in the nucleus after IRF3 gene silencing in KCs by the interference adenovirus.…”

Section: Discussionmentioning

confidence: 76%

IRF3 is an important molecule in the UII/UT system and mediates immune inflammatory injury in acute liver failure

Liu

Zhu

et al. 2016

Oncotarget

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The urotensin II/urotensin receptor (UII/UT) system can mediate inflammatory liver injury in acute liver failure (ALF); however; the related mechanism is not clear. In this study, we confirmed that lipopolysaccharide/D-galactosamine (LPS/D-GalN) induced up-regulation of liver interferon regulatory factor 3 (IRF3) in ALF mice, whereas the UT antagonist urantide inhibited the up-regulated liver IRF3. LPS stimulation induced IRF3 transcription and nuclear translocation and promoted the secretion of interleukin-6 (IL-6), interferon (IFN)-β, and IFN-γ in Kupffer cells (KCs); these effects in LPS-stimulated KCs were inhibited by urantide. Knockdown of IRF3 using an adenovirus expressing an IRF3 shRNA inhibited IFN-β transcription and secretion as well as tumor necrosis factor (TNF)-α and IL-1β secretion from LPS-stimulated KCs; additionally, IL-10 transcription and secretion were promoted in response to LPS. However, LPS-stimulated TNF-α and IL-1β mRNA was not affected in the KCs. The IRF3 shRNA also did not have a significant effect on the NF-κB p65 subunit and p38MAPK protein phosphorylation levels in the nuclei of LPS-stimulated KCs. Therefore, IRF3 expression and activation depended on the signal transduction of the UII/UT system, and played important roles in UII/UT-mediated immune inflammatory injury in the liver but did not affect NF-κB and p38 MAPK activity.

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“…Because the major function of IRF3 is in IFN production, it is thus speculated that the NPHK motif and changes associated with the D → N substitution in IRF3 may facilitate IFN production for aquatic species, specifically through modulations of DNA bindings. In addition, the DPHK (positions 102-105) of human IRF3 is located between nuclear localization (77-89) and nuclear export (139-149) signals [47][48][49][50] . Therefore, although the DPHK motif is conserved among vertebrate species and its substitution to NPHK in three groups of animals is all associated with aquatic life, the exact biological functions of the motif need further experimental exploration.…”

Section: Discussionmentioning

confidence: 99%

Adaptations of Interferon Regulatory Factor 3 with Transition from Terrestrial to Aquatic Life

Angeletti

Hsu

Majo

et al. 2020

Sci Rep

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Interferon regulatory factor 3 (IRF3) and IRF7 are closely related IRF members and the major factors for the induction of interferons, a key component in vertebrate innate immunity. However, there is limited knowledge regarding the evolution and adaptation of those IRFs to the environments. Two unique motifs in IRF3 and 7 were identified. One motif, GASSL, is highly conserved throughout the evolution of IRF3 and 7 and located in the signal response domain. Another motif, DPHK, is in the DNA-binding domain. The ancestral protein of IRF3 and 7 seemed to possess the DPHK motif. In the ray-finned fish lineage, while the DPHK is maintained in IRF7, the motif in IRF3 is changed to NPHK with a D → n amino acid substitution. The D → N substitution are also found in amphibian IRF3 but not in amphibian IRF7. Terrestrial animals such as reptiles and mammals predominantly use DPHK sequences in both IRF3 and 7. However, the D → N substitution in IRF3 DPHK is again found in cetaceans such as whales and dolphins as well as in marsupials. These observations suggest that the D → N substitutions in the IRF3 DPHK motif is likely to be associated with vertebrate's adaptations to aquatic environments and other environmental changes.

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Bipartite Nuclear Localization Signal Controls Nuclear Import and DNA-Binding Activity of IFN Regulatory Factor 3

Cited by 43 publications

References 42 publications

cFLIPL Interrupts IRF3–CBP–DNA Interactions To Inhibit IRF3-Driven Transcription

cFLIPL Interrupts IRF3–CBP–DNA Interactions To Inhibit IRF3-Driven Transcription

IRF3 is an important molecule in the UII/UT system and mediates immune inflammatory injury in acute liver failure

Adaptations of Interferon Regulatory Factor 3 with Transition from Terrestrial to Aquatic Life

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