| Autor: |
Ailenberg, M, Di Ciano-Oliveira, C, Szaszi, K, Dan, Q, Rozycki, M, Kapus, A, Rotstein, O D |
| Jazyk: |
angličtina |
| Rok vydání: |
2015 |
| Předmět: |
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| Popis: |
Dynasore has been used extensively as an inhibitor of clathrin-mediated endocytosis. While studying the role of endocytosis in LPS-induced signalling events, we discovered that dynasore itself induced activation of NF-κB, independently of its effects on endocytosis and without involving the Toll-like receptor 4 signalling pathways. The purpose of this study was to characterize this novel effect and to explore the underlying mechanism of action.We utilized gel electrophoresis, microscopy, gene knockdown and luciferase-based promoter activity to evaluate the effect of dynasore on cell signalling pathways and to delineate the mechanisms involved in its effects,Dynasore activated the NF-κB and IFN-β pathways by activating mitochondrial antiviral signalling protein (MAVS). We showed that MAVS is activated by NOX/Rac and forms high molecular weight aggregates, similar to that observed in response to viral infection. We also demonstrated that dynasore-induced activation of JNK occurs downstream of MAVS and is required for activation of NF-κB and IFN-β.These findings demonstrate a novel effect of dynasore on cell signalling. We describe a novel Rac1-, ROS- and MAVS-mediated signalling cascade through which dynasore dramatically activates NF-κB, mimicking the viral induction of this key inflammatory signalling pathway. Our results call attention to the need for a broader interpretation of results when dynasore is used in its traditional fashion as an inhibitor of clathrin-mediated endocytosis. These results suggest the intriguing possibility that dynasore or one of its analogues might be of value as an antiviral therapeutic strategy or vaccine adjuvant. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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