Regulation of apoptosis by the unfolded protein response - PubMed (original) (raw)

Regulation of apoptosis by the unfolded protein response

Andrew Fribley et al. Methods Mol Biol. 2009.

Abstract

In eukaryotic cells, the endoplasmic reticulum (ER) serves many specialized functions including bio-synthesis and assembly of membrane and secretory proteins, calcium storage and production of lipids and sterols. As a plant for protein folding and posttranslational modification, the ER provides stringent quality control systems to ensure that only correctly folded proteins exit the ER and unfolded or misfolded proteins are retained and ultimately degraded. Biochemical, physiological, and pathological stimuli that interfere with ER function can disrupt ER homeostasis, impose stress to the ER, and subsequently cause accumulation of unfolded or misfolded proteins in the ER lumen. To deal with accumulation of unfolded or misfolded proteins, the cell has evolved highly specific signaling pathways collectively called the "unfolded protein response" (UPR) to restore normal ER functions. However, if the overload of unfolded or misfolded proteins in the ER is not resolved, the prolonged UPR will induce ER stress-associated programmed cell death, apoptosis, to protect the organism by removing the stressed cells. In this chapter, we summarize our current understanding of UPR-induced apoptosis and various methods to detect ER stress and apoptosis in mammalian cells.

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Fig. 1

Fig. 1

The apoptotic pathways regulated by the UPR. In response to ER stress, PERK, and IRE1α are activated through their homodimerization and autophosphorylation. Activated PERK phosphorylates translation initiation factor eIF2α, which can selectively induce expression of proapoptotic transcription factors ATF4 and CHOP. CHOP induces expression of numerous proapoptotic factors including DR5, TRB3, CAVI, and BCL2 family proteins. CHOP can also induce expression of GADD34 and ERO1α, leading to apoptosis by increasing protein synthesis and oxidation in the ER of stressed cells. On activation of the UPR, IRE1α serves as a scaffold protein to form a complex with TRAF2 and ASK1, which subsequently activates the JNK-mediated apoptotic pathway. Furthermore, ER stress can induce BAX and BAK localization and oligomerization at the ER, which promotes calcium release from the ER to the cytosol. Increased cytosolic calcium concentration stimulates calcium uptake into the mitochondrial matrix, which can result in depolarization of the inner membrane and transition of the outer membrane permeability pore. This causes cytochrome c release and Apaf-1-dependent activation of the apoptosome leading to apoptosis. In addition, ER stress may also promote dissociation of TRAF2 from ER membrane-resident procaspase-12, allowing caspase-12 activation to mediate apoptosis. Mito Mitochondria, Cyt-c Cytochrome c, pCP12 Procaspase-12, CP12 Caspase-12, CP9 Caspase-9, CP-3 Caspase-3.

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