The binary switch between life and death of endoplasmic reticulum-stressed beta cells

Abstract

Purpose of review: beta-Cell death is an important pathogenic component of both type 1 and type 2 diabetes. However, the specific molecular pathways and interactions involved in this process are not completely understood. Increasing evidence indicates that a type of cell stress called endoplasmic reticulum stress (ER stress) plays an important role in beta-cell death. In the present article, we discuss a potential paradigm of ER stress-mediated beta-cell death.

Recent findings: Upon ER stress conditions, a signaling network termed the unfolded protein response (UPR) is activated. The UPR regulates adaptive effectors to attenuate ER stress and restore ER homeostasis promoting cell survival. Paradoxically the UPR also regulates apoptotic effectors. When adaptive effectors fail to attenuate ER stress, these apoptotic effectors take into effect leading to cell death. The nature of this switch between life and death is currently under study.

Summary: Depending on the nature of the stress condition, the UPR either protects beta cells or promotes their death. The mechanisms of this switch are not well understood but involve the balance between adaptive and apoptotic factors regulated by the UPR. In the present article, we review examples of this UPR balancing act between life and death and the potential mechanisms involved.

Figure 1. ER stress

In order for proteins to fold properly within the ER, ER homeostasis must be maintained. ER homeostasis is defined by the dynamic balance between the ER protein load and the ER capacity to process this load. ER homeostasis can be perturbed by physiological and pathological stimuli. Disruption of ER homeostasis causes accumulation of unfolded and misfolded proteins in the ER. This condition is referred as ER stress.

Figure 2. The Unfolded Protein Response

Upon ER stress, a signaling network termed the unfolded protein response (UPR) is activated. The UPR is initiated by three master regulators: IRE1, PERK, and ATF6. Together these transducers regulate three types of effectors with the following functions: homeostatic regulation to attenuate ER stress(a), feedback regulation to turn off the UPR when ER homeostasis is restored (b), and apoptotic regulation balancing both survival and death effectors (c).

Figure 3. Binary switch between life and death

The UPR regulates both adaptive/survival and apoptotic effectors. Under tolerable ER stress conditions, the expression and activation of adaptive effectors outweigh the induction of apoptotic effectors therefore promoting cell survival. However under unresolvable ER stress conditions in which ER homeostasis cannot be restored, expression and activation of apoptotic effectors outweigh adaptive effectors leading to cell death. Thus the UPR acts as a binary switch between life and death. The underlying mechanisms of this switch are not well understood but may involve hyperactivation of the UPR sensors, dysregulation of UPR negative feedback loops, and differential regulation of adaptive/survival and apoptotic effectors at both transcriptional and post-transcriptional levels.