Death versus survival: functional interaction between the apoptotic and stress-inducible heat shock protein pathways

Abstract

Induction of heat shock proteins (Hsps) following cellular damage can prevent apoptosis induced by both the intrinsic and the extrinsic pathways. The intrinsic pathway is characterized by mitochondrial outer membrane permeabilization (MOMP), cytochrome c release, apoptosome assembly, and caspase activation. Hsps promote cell survival by preventing MOMP or apoptosome formation as well as via regulation of Akt and JNK activities. Engagement of the TNF death receptors induces the extrinsic pathway that is characterized by Fas-associated death domain-dependent (FADD-dependent) caspase-8 activation or induction of NF-kappaB to promote cellular survival. Hsps can directly suppress proapoptotic signaling events or stabilizing elements of the NF-kappaB pathway to promote cellular survival.

Figure 1

Regulation of the intrinsic pathway by Hsps. Hsps regulate several aspects of the intrinsic apoptotic pathway. These include both direct mediators — e.g., Bax — and indirect regulators — e.g., Akt — of mitochondrial membrane permeabilization to prevent MOMP as well as events downstream of mitochondrial disruption to regulate apoptosome assembly. Caspase-independent cell death may also be affected via Hsp-mediated suppression of AIF activity and inhibition of lysosome permeabilization and cathepsin release.

Figure 2

Regulation of the extrinsic pathway by Hsps. Hsps regulate at multiple points within the signaling pathways activated by ligation of a cell surface death receptor by the appropriate ligand. These include the maintenance of prosurvival signals generated via TNF-mediated activation of NF-κB and suppression of proapoptotic signaling events, e.g., JNK activity and Bid cleavage. Integration of the extrinsic and intrinsic pathways is mediated via the caspase-8–mediated cleavage and activation of Bid as well as activation of JNK, which can impact on numerous molecules that regulate mitochondrial integrity (shown in the shaded area).