Dynasore enhances the formation of mitochondrial antiviral signalling aggregates and endocytosis-independent NF-B activation
Dynasore enhances the formation of mitochondrial antiviral signalling aggregates and endocytosis-independent NF-B activation
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DOI：
10.1111/bph.13162
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发表时间：
2015-08-01
影响因子：
7.3
通讯作者：
Rotstein, O. D.
中科院分区：
文献类型：
--
作者：
Ailenberg, M.;Di Ciano-Oliveira, C.;Rotstein, O. D.
Background and PurposeDynasore 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-B, 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.Experimental ApproachWe 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,Key ResultsDynasore activated the NF-B and IFN- 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-B and IFN-.Conclusion and ImplicationsThese 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-B, 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.
