Autophagic degradation of IRF3 induced by the small-molecule auranofin inhibits its transcriptional and proapoptotic activities.
Autophagic degradation of IRF3 induced by the small-molecule auranofin inhibits its transcriptional and proapoptotic activities.
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DOI：
10.1016/j.jbc.2021.101274
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发表时间：
2021-11
期刊：
影响因子：
--
通讯作者：
Chattopadhyay S
中科院分区：
文献类型：
--
作者：
Glanz A;Chakravarty S;Fan S;Chawla K;Subramanian G;Rahman T;Walters D;Chakravarti R;Chattopadhyay S
广泛表达的转录因子干扰素调节因子3(IRF3)对诱导抗病毒基因如I型干扰素起关键作用。除了转录功能外，IRF3还激活了一条非转录的、促凋亡的信号通路。虽然IRF3的促凋亡功能可以预防病毒感染，但它也参与了引发肝细胞死亡和促进肝脏疾病的有害免疫反应。因此，我们假设IRF3促凋亡活性的小分子抑制剂可以减轻脂肪酸诱导的肝细胞死亡。我们进行了高通量筛选，确定Auranofin是IRF3促凋亡活性的小分子抑制剂。除非转录途径外，Auranofin还抑制IRF3的转录活性。利用人类和小鼠细胞中的生化和遗传工具，我们发现了Auranofin的一个新的作用机制，在这个机制中，它诱导细胞自噬降解IRF3蛋白，从而抑制IRF3的功能。自噬缺陷细胞在Auranofin处理后不能降解IRF3，提示IRF3的自噬降解是调节IRF3活性的一种新途径。利用生理相关的体外模型，我们证明了金诺芬能抑制脂肪酸诱导的肝细胞凋亡。综上所述，Auranofin是一种新的IRF3功能抑制剂，在IRF3有害的疾病中可能是一种潜在的治疗选择。
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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影响因子：
6.7
作者：
Majumdar T;Chattopadhyay S;Ozhegov E;Dhar J;Goswami R;Sen GC;Barik S
通讯作者：
Barik S
影响因子：
6.4
作者：
Pryke KM;Abraham J;Sali TM;Gall BJ;Archer I;Liu A;Bambina S;Baird J;Gough M;Chakhtoura M;Haddad EK;Kirby IT;Nilsen A;Streblow DN;Hirsch AJ;Smith JL;DeFilippis VR
通讯作者：
DeFilippis VR
影响因子：
44.1
作者：
Goswami, Ramansu;Majumdar, Tanmay;Barik, Sailen
通讯作者：
Barik, Sailen
影响因子：
6.4
作者：
Chattopadhyay S;Fensterl V;Zhang Y;Veleeparambil M;Wetzel JL;Sen GC
通讯作者：
Sen GC
DOI：
10.1083/jcb.201503023
发表时间：
2015-09-14
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kimura T;Jain A;Choi SW;Mandell MA;Schroder K;Johansen T;Deretic V
通讯作者：
Deretic V