Cellular response to endoplasmic reticulum stress: a matter of life or death

Boyce, Michael; Yuan, Junying

doi:10.1038/sj.cdd.4401817

Cited by 613 publications

(568 citation statements)

References 167 publications

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“…Active caspase-8 can then directly activate effector caspases such as caspase-3 or can activate the intrinsic apoptosis pathway by cleaving the BH3-only protein Bid resulting in its translocation to the mitochondria (60). A third apoptosis pathway is activated when the endoplasmic reticulum (ER) is stressed (61). This pathway involves many of the same BHcontaining proteins that regulate the mitochondrial pathway.…”

Section: Regulation Of Apoptosismentioning

confidence: 99%

Apoptosis and autophagy: regulatory connections between two supposedly different processes

2007

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Apoptosis and autophagy are genetically-regulated, evolutionarily-conserved processes that regulate cell fate. Both apoptosis and autophagy are important in development and normal physiology and in a wide range of diseases. Recent studies show that despite the marked differences between these two processes, their regulation is intimately connected and the same regulators can sometimes control both apoptosis and autophagy. In this review, I discuss some of these findings, which provide possible molecular mechanisms for crosstalk between apoptosis and autophagy and suggest that it may be useful to think of these processes as different facets of the same cell death continuum rather than completely separate processes. KeywordsAutophagy; Apoptosis; Bcl-2, FADD; Atg 5In the early to mid 1990s there was a rapid increase in our understating about the regulation of apoptosis. Fifteen or so years later we are in the midst of a similarly exciting period for understanding autophagy with very rapid growth of publications on the regulation and function of this process (1). Autophagy (the form of autophagy discussed here is macroautophagy, other forms-microautophagy and chaperone-mediated autophagy share the same lysosomal degradation mechanism but differ in the way that material is delivered to the lysosome) is a degradative process involving sequestration of parts of the cytoplasm in double membrane vesicles (autophagic vesicles or autophagosomes) that fuse with lysosomes forming the autophagolysosome. In the autophagolysosome, the cytoplasmic material that was engulfed is hydrolyzed and the resulting amino acids and other macromolecular precursors can be recycled (2-4), see Fig 1 for a schematic of the process. Autophagy is a mechanism by which organelles are removed and is the primary degradation mechanism for long-lived proteins and thus maintains quality control for proteins and organelles. Autophagy is ubiquitous in eukaryotic cells and important in development and in diverse pathophysiological conditions (5)-for example providing protection against neurodegeneration (6,7), infections (8,9) and tumor development (10-13). Cells that are deficient in autophagy also demonstrate enhanced chromosomal instability (14,15), which may be related to the tumorigenesis associated with autophagy deficiency.Autophagy is important in cell death decisions and can protect cells by preventing them from undergoing apoptosis. For example, increased autophagy in nutrient deprived or growth factorwithdrawn cells allows cell survival (16,17) by inhibiting apoptosis. Autophagy also protects cells from various other apoptotic stimuli (18). It is not clear how autophagy stops cells from undergoing apoptosis; one suggested mechanism is the sequestration of damaged mitochondria (18) thus preventing released cytochrome c from being able to form a functional apoptosome NIH Public Access Autophagic cell death (also known as Type II programmed cell death to distinguish it from apoptosis or Type I programmed cell death) (20-22) has been describ...

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Section: Regulation Of Apoptosismentioning

confidence: 99%

Apoptosis and autophagy: regulatory connections between two supposedly different processes

2007

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“…The initial cellular response following ER stress, also termed the unfolded protein response (UPR), protects the cell through adaptive mechanisms that re-establish normal ER function [1,2]. Given that δPKC inhibition decreased Tm-induced cell death, we sought to determine whether the ER stress pathways are modulated by δPKC.…”

Section: δPkc Activation Is Involved In Er Stress-induced Pathways Inmentioning

confidence: 99%

“…Various pathophysiological stimuli such as hypoxia, glucose deprivation, inhibition of glycosylation, calcium depletion from the lumen, and viral infection induce ER stress and lead to the accumulation of unfolded proteins; this process is collectively called the unfolded protein response (UPR) [1,2]. When ER stress is prolonged and excessive, damaged cells undergo ER stress-induced apoptosis [1,2]. This is a unique pathway, involving activation or increased expression of proteins such as the C/EBP homologous protein, CHOP [3] and caspase 12 [4].…”

Section: Introductionmentioning

confidence: 99%

δPKC participates in the endoplasmic reticulum stress-induced response in cultured cardiac myocytes and ischemic heart

Vallentin

Churchill

et al. 2007

Journal of Molecular and Cellular Cardiology

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The cellular response to excessive endoplasmic reticulum (ER) stress includes the activation of signaling pathways, which lead to apoptotic cell death. Here we show that treatment of cultured cardiac myocytes with tunicamycin, an agent that induces ER stress, causes the rapid translocation of δPKC to the ER. We further demonstrate that inhibition of δPKC using the δPKC-specific antagonist peptide, δV1-1, reduces tunicamycin-induced apoptotic cell death, and inhibits expression of specific ER stress response markers such as CHOP, GRP78 and phosphorylation of JNK. The physiological importance of δPKC in this event is further supported by our findings that the ER stress response is also induced in hearts subjected to ischemia and reperfusion injury and that this response also involves δPKC translocation to the ER. We found that the levels of the ER chaperone, GRP78, the spliced XBP-1 and the phosphorylation of JNK are all increased following ischemia and reperfusion and that δPKC inhibition by δV1-1 blocks these events. Therefore, ischemia-reperfusion injury induces ER stress in the myocardium in a mechanism that requires δPKC activity. Taken together, our data show for the first time that δPKC activation plays a critical role in the ER stressmediated response and the resultant cell death.

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“…The endoplasmic reticulum (ER) comprises about half of the total membrane area and onethird of the newly translated proteins in a typical eukaryotic cell (Boyce and Yuan, 2006;Voeltz dto whom correspondence should be addressed at: Department of Anatomy and Cell Biology, Indiana University School of MedicineEvansville, 8600 University Blvd., Evansville, IN 47712, USA Tel. 812-461-5437;Fax.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, UPR is an adaptative mechanism which promotes survival. However, prolonged UPR activation eventually triggers apoptosis (Boyce and Yuan, 2006;Wu and Kaufman, 2006) A widely accepted and elegant model proposes that when the load of misfolded proteins in the ER exceeds the buffering capacity of the ER chaperone BiP -a condition known as ER stress -UPR is triggered through the depletion of free BiP (Boyce and Yuan, 2006;Hampton, 2003;Harding et al, 2002;Ma and Hendershot, 2002;Shen et al, 2004;Wu and Kaufman, 2006). BiP (Grp78) is a highly conserved and abundant ER chaperone of the Hsp70 family, comprising an N-terminal ATP-ase and a C-terminal protein binding domain, that is essential for the survival of eukaryotic cells (Lee, 2005;Luo et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Decreased ER-associated degradation of α-TCR induced by Grp78 depletion with the SubAB cytotoxin

Lass

Kujawa

McConnell

et al. 2008

The International Journal of Biochemistry & Cell Biology

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HeLa cells stably expressing the α chain of T-cell receptor (αTCR), a model substrate of ERAD (ERassociated degradation), were used to analyze the effects of BiP/Grp78 depletion by the SubAB cytotoxin. SubAB induced XBP1 splicing, followed by JNK phosphorylation, eIF2α phosphorylation, upregulation of ATF3/4 and partial ATF6 cleavage. Other markers of ER stress, including elements of ER-associated degradation (ERAD) pathway, as well as markers of cytoplasmic stress, were not induced. SubAB treatment decreased absolute levels of αTCR, which was caused by inhibition of protein synthesis. At the same time, the half-life of αTCR was extended almost fourfold from 70 min to 210 min, suggesting that BiP normally facilitates ERAD. Depletion ofp97/VCP partially rescued SubAB-induced depletion of αTCR, confirming the role of VCP in ERAD of αTCR. It therefore appears that ERAD of αTCR is driven by at least two different ATPase systems located at two sides of the ER membrane, BiP located on the lumenal side, while p97/ VCP on the cytoplasmic side. While SubAB altered cell morphology by inducing cytoplasm vacuolization and accumulation of lipid droplets, caspase activation was partial and subsided after prolonged incubation. Expression of CHOP/GADD153 occurred only after prolonged incubation and was not associated with apoptosis.

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Cellular response to endoplasmic reticulum stress: a matter of life or death

Cited by 613 publications

References 167 publications

Apoptosis and autophagy: regulatory connections between two supposedly different processes

Apoptosis and autophagy: regulatory connections between two supposedly different processes

δPKC participates in the endoplasmic reticulum stress-induced response in cultured cardiac myocytes and ischemic heart

Decreased ER-associated degradation of α-TCR induced by Grp78 depletion with the SubAB cytotoxin

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