Autophagic degradation of IRF3 induced by the small-molecule auranofin inhibits its transcriptional and proapoptotic activities

Abstract

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Autophagy in Virus Infection: A Race between Host Immune Response and Viral Antagonism

“…We have recently conducted a high-throughput screen to isolate novel small molecules that regulate viral apoptosis [ 54 ]. The screen also isolated auranofin, which inhibited the cellular IFN response [ 55 ]. We showed that auranofin activates the cellular autophagy pathway, degrading the IRF3 protein to block the IFN response ( Figure 4 ).…”

“…Numerous reports suggest that SARS-CoV-2 entry may depend on the autophagy pathway; therefore, these autophagy inhibitors may be used to counteract the replication of the CoV-2 virus. We have shown that auranofin, an anti-rheumatic compound, induces autophagy to degrade IRF3 [ 55 ]. Auranofin has also been shown to inhibit SARS-CoV-2 replication [ 94 ]; whether auranofin degrades a viral protein or a pro-viral host protein in this context will require future evaluation.…”

IRF3 inhibits nuclear translocation of NF-κB to prevent viral inflammation

“…The optimal physiological function of IRF3 in innate antiviral defense depends on its transcriptional and nontranscriptional (nt) activities ( 24 , 35 , 44 , 45 , 64 , 71 ). In addition to the widely studied role of IRF3 as a transcription factor, we demonstrated a proapoptotic function for nt-IRF3, RIPA, which protects the host from viral pathogenesis and contributes to fatty liver diseases ( 35 , 41 , 44 , 45 ).…”

Letter regarding “Auranofin attenuates hepatic steatosis and fibrosis in nonalcoholic fatty liver disease via NRF2 and NF-κB signaling pathways”

“…4 Auranofin inhibited fatty acid-induced hepatocyte apoptosis in an in vitro model by inducing cellular autophagy and thereby degrading IRF3. 5 Auranofin is also known as a pan-inhibitor of thioredoxin reductase (TrxR). 6 By inhibiting TrxR, auranofin induced apoptosis in HCC cells and inhibited tumor growth, together with improved resistance to sorafenib.…”

“…The interferon regulatory factor 3 (IRF3) signaling pathway promotes hepatocyte inflammation and apoptosis in NAFLD [ 4 ]. Auranofin inhibited fatty acid-induced hepatocyte apoptosis in an in vitro model by inducing cellular autophagy and thereby degrading IRF3 [ 5 ].…”