FLASH Meets Nuclear Bodies: CD95 Receptor Signals via a Nuclear Pathway

Eva Krieghoff, Kristijana Milovic-Holm and Thomas G. Hofmann

volume 6 | issue 7

1 April 2007
Pages: 771 - 775

We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:

Download PDF

If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.

The CD95 receptor signals via assembly of a multi-protein complex termed death-inducing signaling complex (DISC) which triggers activation of receptor-bound caspase-8/FLICE molecules. Most cells (type II cells) depend on a mitochondrial amplification pathway to commit apoptosis upon CD95 activation. The caspase-8-binding protein FLICE-associated huge protein (FLASH) has been previously implicated in the regulation of caspase-8 activation at the DISC. However, recent findings demonstrated that FLASH is a Cajal body component and regulates progression through S-phase of the cell cycle in the nucleus. Our recent work identified FLASH as binding partner of the PML nuclear body (PML NB) constituent Sp100 and demonstrated that FLASH partially localizes to PML NBs. Upon CD95 activation FLASH exits the nucleus and translocates to mitochondria where it meets caspase-8 to promote its activation. Our findings reconcile conflicting views on FLASH localization and its role in apoptosis regulation, and suggest that CD95 signals via a nuclear pathway. Potential implications of our findings for understanding FLASH function are discussed.

Authors

Eva Krieghoff

Deutsches Krebsforschungszentrum, Heidelberg, Germany

Kristijana Milovic-Holm

Heinrich-Pette-Institut, Hamburg, Germany

Thomas G. Hofmann