Bak and Bax are killers that can dispatch a cell in no time—once they switch on. Mérino et al. have discovered that two different explanations for the activation of these apoptosis-promoting proteins are both partly right.
Once Bak and Bax flip on, the cell is done for. Mitochondria begin to leak, spilling apoptosis-stimulating molecules that eventually cause cell death. Proteins that carry the BH3 domain, like Bim, trigger apoptosis, but researchers have clashed over how these proteins work. Some scientists argue that certain BH3 proteins turn on Bak and Bax by direct binding. Other researchers support an indirect activation model, in which BH3 proteins neutralize pro-life molecules such as Bcl-2 and Bcl-xL, which normally suppress Bax and Bak. So far, in vitro studies have been inconclusive.
Mérino et al. performed the first in vivo study on Bim, engineering mice to produce the protein with various modifications to its BH3 domain. Bim normally controls blood cell homeostasis, so the researchers used white cell counts and spleen weight as gauges of cell suicide. If the indirect hypothesis is correct, you'd expect that mice carrying Bim versions unable to grab and switch off all the pro-survival proteins would show less apoptosis than normal. But if only indirect activation is important, you'd expect that Bim variants that can neutralize all of the pro-survival molecules but can't activate Bax would have normal levels of apoptosis. However, cell death decreases in both animals. The researchers conclude that both routes are necessary to explain how Bim engages Bax and Bak. The findings might help refine cancer drugs that emulate BH3-carrying proteins.
