Article
- The EMBO Journal (2007) 26, 391 - 401
- doi:10.1038/sj.emboj.7601504
Subject Categories:
FLASH links the CD95 signaling pathway to the cell nucleus and nuclear bodies
Kristijana Milovic-Holm1,3, Eva Krieghoff2, Kirsten Jensen1,a, Hans Will1 and Thomas G Hofmann2,3
- Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie, Hamburg, Germany
- Research Group Cellular Senescence, German Cancer Research Center, Heidelberg, Germany
- These authors contributed equally to this work
Correspondence to:
Thomas G Hofmann, Research Group Cellular Senescence, German Cancer Research Center, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany. Tel.: +49 (0) 6221 424631; Fax: +49 (0) 6221 424902; E-mail: t.hofmann@dkfz.de
aPresent address: Division of Molecular Biosciences, Faculty of Life Sciences, Imperial College, London, UK
Received 29 June 2006; Accepted 15 November 2006
Abstract
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 nucleo-cytoplasmic 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.
Keywords:
- caspase-8,
- CD95 (Fas/APO-1),
- FLASH,
- mitochondria,
- nuclear bodies
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