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Auranofin inhibits IRF3. 30 / 31
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"We investigated whether auranofin, in addition to RIPA, also inhibits the transcriptional activity of IRF3."
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"We showed that auranofin activates the cellular autophagy pathway, degrading the IRF3 protein to block the IFN response (Figure 4)."
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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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"We have shown that auranofin, an anti-rheumatic compound, induces autophagy to degrade IRF3 [55]."
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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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"∗ 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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"A small-molecule, auranofin, promotes autophagic degradation of IRF3 protein, thus blocking both its transcriptional and RIPA functions."
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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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"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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"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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"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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"We uncovered that IRF3 is degraded by auranofin, an FDA-approved compound used to treat rheumatoid arthritis [1]."
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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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"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 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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"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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"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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"Petrasek et al.94 suggested that the STING-IRF3 pathway is an important factor of ALD, that links up ER stress and hepatocyte apoptosistargeting the IRF3 pathway has been proposed as a potential therapeutic approach for ALD.96, 97, 98 It has been reported that a small-molecule auranofin could induce autophagic degradation of IRF3 and inhibit its transcriptional and proapoptotic activities."
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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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"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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"To address this, we tested whether auranofin promotes IRF3 degradation in the absence of RLR stimulation."
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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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"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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"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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"Therefore, we examined whether auranofin-mediated IRF3 degradation depends on the cellular autophagy pathway."
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"Auranofin inhibited fatty acid-induced hepatocyte apoptosis in an in vitro model by inducing cellular autophagy and thereby degrading IRF3 [5]."
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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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"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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"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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"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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