FLASH links the CD95 signaling pathway to the cell nucleus and nuclear bodies
FLASH links the CD95 signaling pathway to the cell nucleus and nuclear bodies
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DOI：
10.1038/sj.emboj.7601504
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发表时间：
2007-01-24
期刊：
影响因子：
11.4
通讯作者：
Hofmann, Thomas G.
中科院分区：
文献类型：
--
作者：
Milovic-Holm, Kristijana;Krieghoff, Eva;Hofmann, Thomas G.
Caspase-8结合蛋白FLICE相关巨蛋白（FLASH）通过促进Caspase-8在死亡诱导信号复合物中的激活来调节死亡受体CD 95诱导的细胞凋亡。在这里，我们发现FLASH与PML核体组分Sp100相互作用，主要存在于细胞核和核体（NB）中。响应于CD 95活化，FLASH离开NB并易位到细胞质中，在那里它在线粒体处积累。FLASH的核质易位需要CD 95诱导的caspase激活，并通过Crm 1依赖的核输出途径促进。通过RNA干扰下调FLASH或抑制其核质穿梭减少了CD 95诱导的细胞凋亡。此外，我们表明，腺病毒抗凋亡Bcl-2家族成员E1 B19 K陷阱FLASH和procaspase-8在线粒体的三元复合物，从而阻断CD 95诱导的caspase-8激活。敲低Sp100通过增强核质FLASH易位增强CD 95激活的细胞凋亡。总之，我们的研究结果表明CD 95通过先前未识别的由FLASH核质易位介导的核途径发出信号。
Caspase-8-binding protein FLICE-associated huge protein ( FLASH) has been proposed to regulate death receptor CD95-induced apoptosis through facilitating caspase-8 activation at the death-inducing signaling complex. Here, we found that FLASH interacts with the PML nuclear body component Sp100 and predominantly resides in the nucleus and nuclear bodies (NBs). In response to CD95 activation, FLASH leaves the NBs and translocates into the cytoplasm where it accumulates at mitochondria. The nucleo-cytoplasmic translocation of FLASH requires CD95-induced caspase activation and is facilitated by the Crm1-dependent nuclear export pathway. Downregulation of FLASH by RNA interference or inhibition of its nucleocytoplasmic shuttling reduced CD95-induced apoptosis. Furthermore, we show that the adenoviral anti-apoptotic Bcl-2 family member E1B19K traps FLASH and procaspase-8 in a ternary complex at mitochondria, thereby blocking CD95-induced caspase-8 activation. Knock-down of Sp100 potentiated CD95-activated apoptosis through enhancing nucleo-cytoplasmic FLASH translocation. In summary, our findings suggest that CD95 signals via a previously unrecognized nuclear pathway mediated by nucleo-cytoplasmic translocation of FLASH.