II- When UPR leads to cell death

According to Oslowsky and Urano (2010)4 there are two types of ER stress conditions, tolerable and unresolvable (Urano, Lecture). Under tolerable ER stress conditions, the UPR promotes cell survival. In contrast, under unresolvable ER stress conditions, the UPR induces cell death.2,4

FOCUS – The Wolfram syndrome

The Wolfram syndrome is a rare autosomal recessive disorder characterized by childhood onset of insulin-dependent diabetes mellitus, followed by optic atrophy, deafness, and death from neurodegeneration in the third or fourth decades.
Postmortem studies revealed a nonautoimmune-linked selective loss of beta-cells consecutive to mutations in the Wolfram syndrome gene 1 (WFS1) which encodes the ER transmembrane protein wolframin. WFS1 suppresses expression
of ATF6 alpha target genes such as BiP and XBP-1 and represses ATF6 alpha-mediated activation of the ER stress response
element (ERSE) promoter. Moreover, WFS1 enhances ATF6 ubiquitination and proteasome-mediated degradation, leading to suppression of ER stress signaling. Consistent with these data, beta-cells from WFS1-deficient mice and lymphocytes from patients with Wolfram syndrome exhibited deregulated ER stress signaling leading to beta-cell death (Urano, Lecture).12

1. Role of CHOP in beta-cell stress and apoptosis

CHOP was identified as an ER stress–induced transcription factor that is a significant mediator of apoptosis in response to ER stress. Chop gene induction is primarily mediated through the PERK/eIF2α/ATF4 UPR pathway, although IRE1α/XBP1 and ATF6α pathways also contribute (Figures 1 and 2). CHOP expression is increased in beta-cells from diabetic mice and humans. Chop deletion in both genetic and diet-induced models of insulin resistance prevents the UPR-induced beta-cell death, improves the capacity of the beta-cell to produce insulin and is associated with increased expression of genes encoding antioxidative stress function.

Thus CHOP is a fundamental factor that links protein misfolding in the ER to oxidative stress and apoptosis in beta-cells under conditions of increased insulin demand (Kaufman, Lecture).11

2. Autophagy

The ubiquitin-proteasome and autophagy-lysosome systems are the two major degradation routes in eukaryotic cells, and the ER is connected to the proteosome and to autophagy during the degradation of misfolded proteins. Hence, ER stress-induced autophagy may have evolved as an alternate mechanism to dispose of misfolded proteins in the ER lumen that cannot be removed through ER associated degradation.
There are various types of autophagy, including micro- and macroautophagy, as well as chaperone-mediated autophagy (CMA), and they differ in their mechanisms and functions (Figure 4) (Cuervo, Lecture). Both micro- and macroautophagy have the capacity to engulf large structures through both selective and non selective mechanisms, whereas CMA degrades only soluble proteins, albeit in a selective manner.

Figure 4. Different types of autophagy. Reprinted by permission from ref 13. © Macmillan Publishers Ltd, 2010.

Figure 4. Different types of autophagy. Reprinted by permission from ref 13. © Macmillan Publishers Ltd, 2010.

Autophagy may either promote cell death through excessive degradation of cellular constituents or protect cells from cell death by providing essential nutrients and removing damaged organelles during cellular stress, depending on the cellular and environmental context. For example, autophagy is induced during nutrient deprivation to deliver intracellular proteins and organelles sequestered in doublemembrane vesicles (autophagosomes) to lysosomes for degradation and use as an energy source. During starvation, macroautophagy is first activated, and then, as starvation persists, cells switch to CMA, which mediates selective targeting of nonessential proteins for degradation to obtain the amino acids required for the synthesis of essential proteins. The intrinsic selectivity of CMA is also well suited for the removal of proteins damaged during stress without perturbing nearby normally functioning forms of the same protein (Cuervo, Lecture). In a context of pancreatic islets stress as during hyperglycemia or chronic exposure to high levels of free fatty acids (FFA) autophagy is activated. Whether or not the upregulated autophagy is contributing to promoting survival or is itself a causative factor in promoting apoptosis remains to be determined (Figure 5).

Figure 5. Summary of some of the roles of ubiquitin-proteasome system and autophagy in pancreatic -cells. Reprinted by permission from ref 15. © The American Physiological Society, 2009.

Figure 5. Summary of some of the roles of ubiquitin-proteasome system and autophagy in pancreatic beta-cells. Reprinted by permission from ref 15. © The American Physiological Society, 2009.

Autophagy has to be tightly regulated so that it is induced when needed, but otherwise maintained at a basal level for normal cellular homeostasis.13 Aberrant regulation of autophagy may be detrimental to metabolism. Indeed, mice with beta-cell-specific deletion of Atg7 (the critical macroautophagy gene autophagy-related 7) showed impaired glucose tolerance and decreased serum insulin level. beta-cell mass and pancreatic insulin content were reduced because of increased apoptosis and decreased proliferation of beta-cells. Thus autophagy is necessary to maintain
structure, mass and function of pancreatic beta-cells, and its impairment causes insulin deficiency and hyperglycemia because of abnormal turnover and function of cellular organelles (Lee, Lecture).14 Insulin and its downstream molecules such as mTOR/ S6K1 are well-known inhibitors of autophagy, whereas glucagon induces it, suggesting that alterations in this control may be observed in insulin-resistant states such as diabetes. Interestingly, autophagy could be involved in the regulation of the number of insulin secretory granules and in the degradation of beta-cells mitochondria (Volchuk, Lecture).15

“The Stressed Beta-Cell”
I- ER and the canonical unfolded protein response (UPR)
II- When UPR leads to cell death
III- Cellular stress in type 2 diabetes
IV- The mitochondria and cellular stress
V- Therapeutic targeting of ER dysfunction
VI- Conclusions