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Auranofin inhibits IRF3. 37 / 37
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"IRF3 activation induced by MyD88 independent signaling components, TRIF and TBK1, was also downregulated by auranofin."
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"In this study, we demonstrated that auranofin induced cellular autophagy to degrade IRF3 protein; as a consequence, IFNβ production and IRF3-driven apoptosis were impaired."
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"Overall, our results suggest that auranofin treatment can cause the degradation of IRF3 protein in human and mouse cells.Auranofin activates the cellular autophagy pathway to induce IRF3 degradation Degradation of IRF3 protein is a key biochemical event regulating virus replication and host inflammatory response.Many viruses also trigger proteasomal degradation of IRF3 to facilitate viral replication (22, 23) ."
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"Auranofin inhibited nuclear factor-kappaB and interferon (IFN) regulatory factor 3 (IRF3) activation induced by polyinosinic-polycytidylic acid (poly [I : C])."
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"Together, auranofin inhibits both the proapoptotic and transcriptional activities of IRF3 in multiple cell types.To determine the molecular mechanism of auranofin-mediated inhibition of IRF3 activities, we investigated the effect of auranofin on IRF3 phosphorylation (p-IRF3), which is critical for the transcriptional activity of IRF3."
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"Autophagic degradation of IRF3 induced by the small-molecule auranofin inhibits its transcriptional and proapoptotic activities.Recently, we performed a high-throughput screen of a library of FDA-approved drugs to isolate small-molecule activators of RIPA (19)."
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"Overall, our results suggest that auranofin treatment can cause the degradation of IRF3 protein in human and mouse cells.Degradation of IRF3 protein is a key biochemical event regulating virus replication and host inflammatory response."
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"In addition to the nontranscriptional apoptotic pathway, auranofin also inhibited the transcriptional activity of IRF3."
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"In MDA-MB-453 cells, RLR stimulation caused robust degradation of activated IRF3, and the auranofin treatment promoted the RLR-induced degradation of IRF3 protein (Fig. 3B)."
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"In RLR-stimulated cells, the induction of IFIT3 (Fig. 2A) and IFIT1 (Fig. 2B), the IRF3-dependent genes, was strongly inhibited by auranofin in HT1080 cells."
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"To address this , we tested whether auranofin promotes IRF3 degradation in the absence of RLR stimulation ."
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"To inquire whether auranofin inhibits IRF3 activity or triggers the degradation of IFIT proteins, we analyzed the mRNA induction of the IRF3 target genes."
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"Therefore, we examined whether auranofin-mediated IRF3 degradation depends on the cellular autophagy pathway."
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"Autophagic degradation of IRF3 by auranofin inhibits palmitic-acid-induced apoptotic cell death in human hepatocytes ."
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"To validate the auranofin-induced degradation of IRF3 protein, we chose RAW264.7 mouse macrophages, in which auranofin treatment also caused degradation of IRF3 protein in both dose and time-dependent manner (Fig. 3, F and G)."
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"Because IRF3 plays a proapoptotic role in hepatocyte apoptosis , we examined whether auranofin induces IRF3 degradation , as observed earlier in nonhepatic cells , to inhibit PA-induced apoptosis ."
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"Because IRF3 plays a proapoptotic role in hepatocyte apoptosis, we examined whether auranofin induces IRF3 degradation, as observed earlier in nonhepatic cells, to inhibit PA-induced apoptosis."
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"∗ indicates p < 0.05.Figure 7: Autophagic degradation of IRF3 by auranofin inhibits palmitic-acid-induced apoptotic cell death in human hepatocytes.A, Huh7 cells were treated with palmitic acid (PA) or vehicle (bovine serum albumin, BSA) for 24 h, when the caspase-3 activity was measured."
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"Autophagic degradation of IRF3 induced by the small-molecule auranofin inhibits its transcriptional and proapoptotic activities.The ubiquitously expressed transcription factor interferon (IFN) regulatory factor 3 (IRF3) is critical for the induction of antiviral genes, e.g., type-I IFN."
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"Collectively, our results suggest that auranofin inhibits the fatty-acid-induced hepatocyte apoptosis by causing autophagic degradation of IRF3 protein.Given the critical role of IRF3 in innate immune defense, identifying both positive and negative modulators of the IRF3 functions is desirable."
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"* indicates p < 0.05.Autophagic degradation of IRF3 by auranofin inhibits palmitic-acid-induced apoptotic cell death in human hepatocytes."
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"To address this, we tested whether auranofin promotes IRF3 degradation in the absence of RLR stimulation."
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"We uncovered that IRF3 is degraded by auranofin , an FDA-approved compound used to treat rheumatoid arthritis [ 1 ] ."
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"We recently revealed that IRF3 is degraded by a small molecule, auranofin, by activating the cellular macroautophagy/autophagy pathway."
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"We uncovered that IRF3 is degraded by auranofin, an FDA-approved compound used to treat rheumatoid arthritis [1]."
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"Autophagic degradation of IRF3 induced by the small molecule auranofin inhibits its transcriptional and pro-apoptotic activities."
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"Our results indicate that auranofin treatment caused degradation of inactive IRF3 protein in a time-dependent manner in different cell types (Fig. 3, C–E)."
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"Finally, we examined whether auranofin-mediated IRF3 degradation was autophagy-dependent; genetic inhibition of autophagy in the shATG5 cells also protected IRF3 from auranofin-induced degradation (Fig. 4G)."
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"To inquire whether auranofin inhibits IRF3 activity or triggers the degradation of IFIT proteins , we analyzed the mRNA induction of the IRF3 target genes ."
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"Auranofin activates the autophagy pathway to trigger the degradation of IRF3 but not related proteins, e.g., NFKB/NF-κB, STAT1, and MAPK14/p38."
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"These results led to the hypothesis that auranofin promotes the degradation of IRF3 protein, thereby causing the inhibition of its activities."
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"We investigated whether auranofin, in addition to RIPA, also inhibits the transcriptional activity of IRF3."
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"Together, our results indicate that the cellular autophagy pathway is involved in the auranofin-mediated degradation of IRF3 protein.In the next series of experiments, we tested whether autophagy-mediated degradation of IRF3 protein inhibits its activities."
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"Therefore, auranofin is a novel inhibitor of the IRF3-mediated apoptotic pathway.In addition to triggering apoptosis, IRF3 functions as a transcription factor to induce the antiviral genes, such as IFNβ and ISGs (20)."
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"A small-molecule, auranofin, promotes autophagic degradation of IRF3 protein, thus blocking both its transcriptional and RIPA functions."
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"Figure 7 : Autophagic degradation of IRF3 by auranofin inhibits palmitic-acid-induced apoptotic cell death in human hepatocytes.A , Huh7 cells were treated with palmitic acid ( PA ) or vehicle ( bovine serum albumin , BSA ) for 24 h , when the caspase-3 activity was measured ."
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"In summary, auranofin inhibits the transcriptional activity of IRF3, mediated by TLR and RLR signaling pathways, in both human and mouse cells."
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