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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. In addition to its transcriptional function, IRF3 also activates a nontranscriptional, proapoptotic signaling pathway. While the proapoptoti...

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Autores principales: Glanz, Anna, Chakravarty, Sukanya, Fan, Shumin, Chawla, Karan, Subramanian, Gayatri, Rahman, Tia, Walters, Dean, Chakravarti, Ritu, Chattopadhyay, Saurabh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8531670/
https://www.ncbi.nlm.nih.gov/pubmed/34619149
http://dx.doi.org/10.1016/j.jbc.2021.101274
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author Glanz, Anna
Chakravarty, Sukanya
Fan, Shumin
Chawla, Karan
Subramanian, Gayatri
Rahman, Tia
Walters, Dean
Chakravarti, Ritu
Chattopadhyay, Saurabh
author_facet Glanz, Anna
Chakravarty, Sukanya
Fan, Shumin
Chawla, Karan
Subramanian, Gayatri
Rahman, Tia
Walters, Dean
Chakravarti, Ritu
Chattopadhyay, Saurabh
author_sort Glanz, Anna
collection PubMed
description The ubiquitously expressed transcription factor interferon (IFN) regulatory factor 3 (IRF3) is critical for the induction of antiviral genes, e.g., type-I IFN. In addition to its transcriptional function, IRF3 also activates a nontranscriptional, proapoptotic signaling pathway. While the proapoptotic function of IRF3 protects against viral infections, it is also involved in harmful immune responses that trigger hepatocyte cell death and promote liver disease. Thus, we hypothesized that a small-molecule inhibitor of the proapoptotic activity of IRF3 could alleviate fatty-acid-induced hepatocyte cell death. We conducted a high-throughput screen, which identified auranofin as a small-molecule inhibitor of the proapoptotic activity of IRF3. In addition to the nontranscriptional apoptotic pathway, auranofin also inhibited the transcriptional activity of IRF3. Using biochemical and genetic tools in human and mouse cells, we uncovered a novel mechanism of action for auranofin, in which it induces cellular autophagy to degrade IRF3 protein, thereby suppressing IRF3 functions. Autophagy-deficient cells were unable to degrade IRF3 upon auranofin treatment, suggesting that the autophagic degradation of IRF3 is a novel approach to regulate IRF3 activities. Using a physiologically relevant in vitro model, we demonstrated that auranofin inhibited fatty-acid-induced apoptotic cell death of hepatocytes. In summary, auranofin is a novel inhibitor of IRF3 functions and may represent a potential therapeutic option in diseases where IRF3 is deleterious.
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spelling pubmed-85316702021-10-28 Autophagic degradation of IRF3 induced by the small-molecule auranofin inhibits its transcriptional and proapoptotic activities Glanz, Anna Chakravarty, Sukanya Fan, Shumin Chawla, Karan Subramanian, Gayatri Rahman, Tia Walters, Dean Chakravarti, Ritu Chattopadhyay, Saurabh J Biol Chem Research Article The ubiquitously expressed transcription factor interferon (IFN) regulatory factor 3 (IRF3) is critical for the induction of antiviral genes, e.g., type-I IFN. In addition to its transcriptional function, IRF3 also activates a nontranscriptional, proapoptotic signaling pathway. While the proapoptotic function of IRF3 protects against viral infections, it is also involved in harmful immune responses that trigger hepatocyte cell death and promote liver disease. Thus, we hypothesized that a small-molecule inhibitor of the proapoptotic activity of IRF3 could alleviate fatty-acid-induced hepatocyte cell death. We conducted a high-throughput screen, which identified auranofin as a small-molecule inhibitor of the proapoptotic activity of IRF3. In addition to the nontranscriptional apoptotic pathway, auranofin also inhibited the transcriptional activity of IRF3. Using biochemical and genetic tools in human and mouse cells, we uncovered a novel mechanism of action for auranofin, in which it induces cellular autophagy to degrade IRF3 protein, thereby suppressing IRF3 functions. Autophagy-deficient cells were unable to degrade IRF3 upon auranofin treatment, suggesting that the autophagic degradation of IRF3 is a novel approach to regulate IRF3 activities. Using a physiologically relevant in vitro model, we demonstrated that auranofin inhibited fatty-acid-induced apoptotic cell death of hepatocytes. In summary, auranofin is a novel inhibitor of IRF3 functions and may represent a potential therapeutic option in diseases where IRF3 is deleterious. American Society for Biochemistry and Molecular Biology 2021-10-05 /pmc/articles/PMC8531670/ /pubmed/34619149 http://dx.doi.org/10.1016/j.jbc.2021.101274 Text en © 2021 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Glanz, Anna
Chakravarty, Sukanya
Fan, Shumin
Chawla, Karan
Subramanian, Gayatri
Rahman, Tia
Walters, Dean
Chakravarti, Ritu
Chattopadhyay, Saurabh
Autophagic degradation of IRF3 induced by the small-molecule auranofin inhibits its transcriptional and proapoptotic activities
title Autophagic degradation of IRF3 induced by the small-molecule auranofin inhibits its transcriptional and proapoptotic activities
title_full Autophagic degradation of IRF3 induced by the small-molecule auranofin inhibits its transcriptional and proapoptotic activities
title_fullStr Autophagic degradation of IRF3 induced by the small-molecule auranofin inhibits its transcriptional and proapoptotic activities
title_full_unstemmed Autophagic degradation of IRF3 induced by the small-molecule auranofin inhibits its transcriptional and proapoptotic activities
title_short Autophagic degradation of IRF3 induced by the small-molecule auranofin inhibits its transcriptional and proapoptotic activities
title_sort autophagic degradation of irf3 induced by the small-molecule auranofin inhibits its transcriptional and proapoptotic activities
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8531670/
https://www.ncbi.nlm.nih.gov/pubmed/34619149
http://dx.doi.org/10.1016/j.jbc.2021.101274
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