A Convoluted Way to Die

velopment is initiated by transcriptional upregulation of Ivelisse Sánchez and Junying Yuan* Egl-1, another BH3-only member of the BCL-2 family Department of Cell Biology that acts by inhibiting Ced-9, an antiapoptotic member Harvard Medical School of the BCL-2 family (Conradt and Horvitz, 1998). 240 Longwood Avenue BIM may not be the only BH3-only member that is Boston, Massachusetts 02115 induced by trophic factor deprivation. Previously, DP5/ Hrk, another BH3-only member of the BCL-2 family, was shown to be induced in rat sympathetic neurons upon NGF deprivation and in cortical neurons stimulated by The neurons that fail to establish proper connections amyloid b protein (reviewed in Yuan and Yankner, 2000). with their respective postsynaptic targets die naturally Although it is not clear if inhibition of DP5/Hrk may reduring development due to the lack of sufficient trophic duce neuronal cell death, coinduction of DP5/Hrk and BIM support. The first hint that such naturally occurring neusuggests that multiple BH3-only members of the BCL-2 ronal cell death requires the active participation of neufamily may be induced in order for neurons to die. rons came from the seminal work by Eugene Johnson The BH3-Only Members of BCL-2 Family: Critical and colleagues who showed that sympathetic neuronal Intracellular Mediators of Death Signaling cell death induced by NGF deprivation can be inhibited The BH3-only members of BCL-2 family include Egl-1, by macromolecular synthesis inhibitors such as cycloBIM, Hrk/DP5, BIK, BID BAD, and NOXA, and the list is heximide and actinomycin D (reviewed in Yuan and Yankstill expanding (Huang and Strasser, 2000). Although ner, 2000). These findings suggested that certain deathwhat identifies these killer proteins as a group is only a inducing molecules must be synthesized in order for limited homology within a stretch of nine–amino acid neurons to die. The identity of such molecules and how sequence, termed the “BH3 domain,” previous structhey function to induce neuronal death have been the tural studies of BID suggest that they may share a sursubject of many studies and remained largely a mystery prising high level of homology with other members of until recently. It turns out that one of these molecules the BCL-2 family in their tertiary structures, consisting is none other than BIM (the BCL-2 interacting mediator of four hydrophobic a helixes surrounding two central of cell death), a BH3-only member of the BCL-2 family. hydrophobic helixes, which are the business center of Previous works from Andrew Strasser’s lab have shown the molecule (Chou et al., 1999; McDonnell et al., 1999). that there are three BIM isoforms; BIMS, BIML, and BIMEL, Their overall structural similarities indicate that they may all of which are proapoptotic to different extents (O’Conact in similar fashion to regulate cell death. nor et al., 1998). In this issue of Neuron, two papers from Previous works from Johnson’s lab have shown that the Eugene Johnson and Jonathan Ham laboratories, the protein synthesis step in trophic factor–deprived respectively (Whitfield et al., 2001; Putcha et al., 2001), sympathetic neurons is required to induce the translocashow that BIMEL is induced in a variety of neuronal cell tion of BAX, a proapoptotic member of the BCL-2 family, death paradigms including sympathetic neurons upon from cytosol to mitochondria, that is critical for neurons removal of NGF, neonatal sciatic nerve axotomy, and to die (Putcha et al., 1999). Bax sympathetic neurons K-deprived cerebellar granule neurons. Furthermore, are highly resistant to trophic factor deprivation–induced they show that inhibition of BIM by antisense and gecell death (Miller et al., 1997). Therefore, one possibility is netic knockout approaches significantly reduced symthat transcriptionally upregulated BIM or BIM-like molepathetic neuron death induced by NGF deprivation. cule(s) are responsible for mitochondrial translocation Thus, BIM clearly fits the criteria of a death-inducing of BAX. Although it has not been examined whether BAX molecule that is synthesized in order for neurons to die. remains cytosolic in Bim knockout neurons, Johnson and colleagues (Putcha et al., 2001) found that induced Upregulation of BIM expression during apoptosis is BIM resides in the mitochondria as an integral memnot limited to neurons: BIM is also induced in cytokinebrane protein, which makes it unlikely that BIM is redeprived murine IL3-dependent cells (Shinjyo et al., sponsible for the translocation of BAX from the cytosol 2001). In addition, BIM is essential for the execution to mitochondria. Since BIM has been shown to interact of trophic factor deprivation–induced apoptosis in the with BCL-2 and BCL-W, but not BAX, BIM may function lymphoid cell lineages (Bouillet et al., 1999). Thus, all to inactivate BCL-2-related antiapoptotic proteins and trophic factor deprivation–induced apoptosis in differcontribute indirectly to the multimerization and integraent mammalian cell types may be regulated by BIM or tion of BAX into the mitochondrial outer membrane. BIM-like BH3-only members of the BCL-2 family. Since If BIM does not act by inducing BAX translocation, BIM most likely acts by inhibiting proapoptotic members then there must be another factor that needs to be synof the BCL-2 family (O’Connor et al., 1998), this demonthesized in trophic factor–deprived sympathetic neustrates again the beautiful evolutionary convergence on rons to induce BAX translocation. Thus, the protein synthe mechanism of apoptosis from C. elegans to mamthesis step in trophic factor–deprived sympathetic mals, as programmed cell death during C. elegans deneurons may have produced several death-inducing activities that act to coordinate the death process. Interestingly, BID, another BH3-only member of the BCL-2 fam* To whom correspondence should be addressed (e-mail: jyuan@