Modulation of apoptosis sensitivity through the interplay with autophagic and proteasomal degradation pathways

Abstract

Autophagic and proteasomal degradation constitute the major cellular proteolysis pathways. Their physiological and pathophysiological adaptation and perturbation modulates the relative abundance of apoptosis-transducing proteins and thereby can positively or negatively adjust cell death susceptibility. In addition to balancing protein expression amounts, components of the autophagic and proteasomal degradation machineries directly interact with and co-regulate apoptosis signal transduction. The influence of autophagic and proteasomal activity on apoptosis susceptibility is now rapidly gaining more attention as a significant modulator of cell death signalling in the context of human health and disease. Here we present a concise and critical overview of the latest knowledge on the molecular interplay between apoptosis signalling, autophagy and proteasomal protein degradation. We highlight that these three pathways constitute an intricate signalling triangle that can govern and modulate cell fate decisions between death and survival. Owing to rapid research progress in recent years, it is now possible to provide detailed insight into the mechanisms of pathway crosstalk, common signalling nodes and the role of multi-functional proteins in co-regulating both protein degradation and cell death.

Figure 1

A signalling triangle of autophagy, the UPS and apoptosis modulates cell death susceptibility and balances cell death versus survival decisions

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

Figure 3

Proposed components and composition of a caspase-8 activation platform that forms as a signalling node in the interplay of apoptosis, autophagy and the UPS. On the basis of the accumulated experimental evidence of a number of recent studies, the molecular composition and formation mechanism for a novel caspase-8 activation platform is proposed. The formation of the activation platform requires the interplay of a number of Atg proteins and LC3 as well as core proteins that are relevant also during extrinsic apoptosis induction (Fadd, cFLIP, caspase-8). Lipidated LC3II, together with Atg5-12, Atg16, Fadd and p62 appear to contribute to caspase-8 activation and may form a multi-molecular activation platform on autophagosomal membranes. Details on these interactions and their implications for caspase-8 activation and apoptosis induction are provided in the text

Figure 4

Perturbation–response relationships in the apoptosis–autophagy–UPS triangle. An overview of the perturbations and their consequences in the apoptosis–autophagy–UPS triangle demonstrates that signalling responses can be either definite or ambiguous. Downward red arrows represent inhibitions or reductions, upward green arrows indicate activation or upregulations. Care therefore needs to be taken when investigating and interpreting experimental data on cause and effect relationships, and when generalising such findings