Accumulation of the pro-apoptotic factor Bak is controlled by antagonist factor Mcl-1 availability

Apoptosis has become recognized as a crucial mechanism
involved in a wide range of physiological and pathological
processes. Following an initial pro-apoptotic signal,
controlling phases allow the cell to reinforce or downgrade
signals leading to the irrevocable entry into apoptosis. Bak
(Bcl-2-antagonist killer) is a mitochondrial pore-forming
pro-apoptotic effector inhibited through titration by the antiapoptotic
protein Mcl-1 (Myeloid cell leukemia-1). Viruses
have taken advantage of proteasome-dependent degradation
of Bak as a mechanism to prevent apoptosis in infected
cells. It is not clear however whether regulation of Bak protein
level is involved in other physiological processes. In this
report, we show that Mcl-1 level is paralleled by Bak while
a Mcl-1 non-interacting mutant of Bak does not accumulate
in cells. This mechanism is proteasome independent.
Following serum withdrawal, Bak accumulation becomes
independent of Mcl-1 level and cells are sensitized to proapoptotic
stimuli. Based on these results, we propose that
regulation of Mcl-1-Bak steochiometry is a control mechanism
used as a checkpoint to prevent or allow entry into
apoptosis.