Bim plays apoptosis offense

A revision of competing ideas about programmed cell death is in order, according to results from Weber et al. (page 625). The work gets a step closer to nailing down the controversial role of the BH3-only family of proteins as playing offense on the pro-death team of apoptotic proteins, rather than defense against the opposing protective agents.

Three groups of apoptosis proteins control a cell's life-or-death fate: Bax/Bak (the executioners) and BH3-only proteins are pro-apoptotic, whereas a subset of Bcl-2 proteins are anti-apopototic. But researchers have had a hard time deciding how the BH3-only proteins, a group that includes Bim, factor into the equation. One side argues that BH3-only proteins bind to Bax/Bak directly to turn on these killing machines. Another line of thinking has the BH3-only proteins running interference for the killers by soaking up and neutralizing the protective Bcl-2 members.

Here, Weber and colleagues introduce clues that suggest a bit of rethinking may be in order. An inducible version of Bim showed that high levels of Bim caused death without coming into contact with Bcl-2 protectors. In yeast that lacked any Bcl-2 proteins, Bim still enhanced the death action of Bax. This enhancement appeared to work by helping Bax insert into the mitochondrial membrane—but without a direct interaction.

The authors speculate that the translocation of Bim and other BH3-only proteins into the mitochondrial membrane sets up their pro-death teammate Bax to join them there. In any event, neither the direct-binding model or the displacement model appears to explain entirely how these proteins play the game.