Figure 2
Crosstalk and interactions in the autophagy–apoptosis and UPS–apoptosis interplays. (a) The major components regulating the interplay of autophagy and apoptosis at the level of Beclin-1 and Bcl-2 family members are shown. Unphosphorylated Bim forms a complex with Beclin-1 and the adaptor protein LC8. Free Beclin-1 can be antagonised by anti-apoptotic Bcl-2 family proteins. The latter can be inhibited by phosphorylated Bim and other BH3-only proteins such as Bad and Bnip3, resulting in liberation of Beclin-1 and induction of autophagy. Phosphorylated Bim can activate Bax and Bak, resulting in caspase activation and apoptosis execution. Beclin-1 can be cleaved by effector caspases and is thereby converted to a pro-apoptotic protein. The interaction of positive and negative regulatory processes therefore determines the induction of autophagy and/or apoptosis. (b) The main processes and players involved in the control and modulation of apoptosis by proteasomal activity are displayed. (i) The steady state expression amounts of both pro- and anti-apoptotic proteins are co-regulated by proteasomal activity. Pro-apoptotic proteins that are strongly regulated include Bax and the BH3-only proteins Bim, Noxa and Bik, anti-apoptotic proteins include Mcl-1, cFLIP and cIAPs. (ii) Inhibition of proteasomal activity disturbs the steady state. As a consequence, high turn-over proteins accumulate. In addition, proteasome inhibition can actively induce the expression of pro-apoptotic proteins. Proteasome inhibition can induce apoptosis and is accompanied by compensatory induction of autophagy
