XIAP levels drop after NGF withdrawal.

It is not easy to convince sympathetic neurons to commit suicide. Potts et al. (page 789) now show that a caspase inhibitor called XIAP acts as a safety brake so that these terminally differentiated cells do not take the death decision too lightly.

Earlier studies established that injection of cytochrome c, which is normally released from mitochondria to activate caspases and thus apoptosis, can kill most cell types but not sympathetic neurons. This resistance can be overcome by coinjection with excess Smac, which shuts down caspase inhibitors including XIAP. Potts et al. now show that cells lacking XIAP no longer need Smac, and succumb to cytochrome c injection alone.

This clean result from a single gene deletion was surprising because there are a number of XIAP-like inhibitors, or IAPs, that have until now been largely undifferentiated. The entire family of proteins has been plagued by the absence of knockout phenotypes (although their overexpression clearly inhibits apoptosis); this situation has now been rectified for XIAP.

As postmitotic cells that are not easily replaced, sympathetic neurons must resist most toxic insults without resorting to apoptosis. These insults can breach mitochondria, releasing not only cytochrome c but also Smac. But Potts et al. find that these endogenous levels of Smac are not sufficient to shut off XIAP, unlike the excess injected Smac.

Only when survival factors such as NGF are withdrawn do the neurons finally give up the ghost. The mechanism of XIAP down-regulation is not yet clear. After NGF withdrawal, XIAP mRNA levels are reduced. But XIAP protein degradation may also occur, as XIAP levels drop more after NGF withdrawal than after a protein synthesis shut-off with cycloheximide. A mystery also surrounds the specificity of the phenotype: both why XIAP is the critical IAP in sympathetic neurons, and why the similar levels of XIAP found in other cell types do not have a similar safety brake effect. ▪