FLASH meets nuclear bodies - CD95 receptor signals via a nuclear pathway

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.