Coupling endoplasmic reticulum stress to the cell death program: role of the ER chaperone GRP78

Rao, Rammohan V.; Peel, Alyson; Logvinova, Anna; Río, Gabriel del; Hermel, Evan; Yokota, Takanori; Goldsmith, Paul C.; Ellerby, Lisa M.; Ellerby, H. Michael; Bredesen, Dale E.

doi:10.1016/s0014-5793(02)02289-5

Cited by 533 publications

(450 citation statements)

References 41 publications

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“…Caspase-7 has been previously reported to localize in the ER and nucleus during apoptotic stimulation. 41,42 Colocalization of caspase-2 and -7 with Htt is consistent with both our immunoprecipitation results and our proposed role of these caspases in the initiation of Httmediated cell death.…”

Section: Inhibition Of Htt-induced Polyglutamine Repeatdependent Cellsupporting

confidence: 91%

Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease

et al. 2004

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Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder resulting in selective neuronal loss and dysfunction in the striatum and cortex. The molecular pathways leading to the selectivity of neuronal cell death in HD are poorly understood. Proteolytic processing of full-length mutant huntingtin (Htt) and subsequent events may play an important role in the selective neuronal cell death found in this disease. Despite the identification of Htt as a substrate for caspases, it is not known which caspase(s) cleaves Htt in vivo or whether regional expression of caspases contribute to selective neuronal cells loss. Here, we evaluate whether specific caspases are involved in cell death induced by mutant Htt and if this correlates with our recent finding that Htt is cleaved in vivo at the caspase consensus site 552. We find that caspase-2 cleaves Htt selectively at amino acid 552. Further, Htt recruits caspase-2 into an apoptosome-like complex. Binding of caspase-2 to Htt is polyglutamine repeat-length dependent, and therefore may serve as a critical initiation step in HD cell death. This hypothesis is supported by the requirement of caspase-2 for the death of mouse primary striatal cells derived from HD transgenic mice expressing full-length Htt (YAC72). Expression of catalytically inactive (dominant-negative) forms of caspase-2, caspase-7, and to some extent caspase-6, reduced the cell death of YAC72 primary striatal cells, while the catalytically inactive forms of caspase-3, -8, and -9 did not. Histological analysis of post-mortem human brain tissue and YAC72 mice revealed activation of caspases and enhanced caspase-2 immunoreactivity in medium spiny neurons of the striatum and the cortical projection neurons when compared to controls. Further, upregulation of caspase-2 correlates directly with decreased levels of brain-derived neurotrophic factor in the cortex and striatum of 3-month YAC72 transgenic mice and therefore suggests that these changes are early events in HD pathogenesis. These data support the involvement of caspase-2 in the selective neuronal cell death associated with HD in the striatum and cortex.

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Section: Inhibition Of Htt-induced Polyglutamine Repeatdependent Cellsupporting

confidence: 91%

Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease

et al. 2004

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“…The dissociation of Ire1-a and procaspase-12 from GRP-78 after acidosis suggests this as the mechanism by which the ER stress response is triggered by acidosis. Caspase-12 normally exists in an inactive, 60 kDa procaspase form that is bound to ER membranes in association with GRP-78 (Rao et al, 2002b). During ER stress, caspase-12 dissociates from the ER membrane and is cleaved first to a 46 kDa fragment and subsequently to an active, 35 kDa fragment Rao et al, 2002b).…”

Section: Discussionmentioning

confidence: 99%

“…Caspase-12 normally exists in an inactive, 60 kDa procaspase form that is bound to ER membranes in association with GRP-78 (Rao et al, 2002b). During ER stress, caspase-12 dissociates from the ER membrane and is cleaved first to a 46 kDa fragment and subsequently to an active, 35 kDa fragment Rao et al, 2002b). The expression levels of these caspase-12 species are consequently influenced by the rates of both de novo procaspase-12 synthesis and procaspase-12 cleavage.…”

Section: Discussionmentioning

confidence: 99%

“…Normally, Ire1-a and procaspase-12 are both bound to GRP-78 on ER membranes ; Caspase-12-mediated astrocyte death K Aoyama et al Rao et al, 2002b). During ER stress, GRP-78 binds to misfolded proteins in the ER lumen and releases Ire1-a and procaspase-12, which together lead to the cellular ER stress response.…”

Section: Acidosis Induces Dissociation Of Ire1-a and Procaspase-12 Frmentioning

confidence: 99%

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Acidosis Causes Endoplasmic Reticulum Stress and Caspase-12-Mediated Astrocyte Death

Aoyama

Burns

Suh

et al. 2005

J Cereb Blood Flow Metab

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Endoplasmic reticulum (ER) stress leads to activation of caspase-12, which in turn can lead to activation of caspase-3 and cell death. Here we report that transient acidosis induces ER stress and caspase-12-mediated cell death in mouse astrocytes. After a 3-hour incubation at pH 6.0, astrocytes exhibited delayed cell death associated with nuclear condensation and fragmentation. Cell death was reduced by the protein synthesis inhibitor cycloheximide, further suggesting an active cell death program. Acidosis increased the expression of the ER chaperone protein GRP-78, indicative of ER stress. Acidosis also increased caspase-12 mRNA expression, caspase-12 protein expression, cleavage of caspase-12 to its active form, and activation of caspase-3. Each of these effects was suppressed in astrocytes pretreated with caspase-12 antisense phosphorodiamidate morpholino oligodeoxynucleotides (PMOs). Caspase-12 antisense PMOs also reduced the cell death induced by acidosis. Immunoprecipitation studies showed dissociation of both caspase-12 and Ire1-a from GRP-78, thereby suggesting a mechanism by which acidosis can initiate the ER stress response. To evaluate caspase-12 activation in vivo, rats were subjected to middle cerebral artery ischemiareperfusion. Immunostaining of brain sections harvested 24 hours later showed increased caspase-12 expression and nuclear condensation in astrocytes of the periinfarct region exposed to acidosis during ischemia. These findings suggest that acidosis induces ER stress and caspase-12 activation, and that these changes may contribute to delayed cell death after ischemia.

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“…15,16 The biochemical activation of apoptosis occurs via two major pathways: the intrinsic pathway, initiated by the mitochondrial release of cytochrome c, resulting in the activation of caspase-9; and the extrinsic pathway, initiated by the activation of cell surface death receptors such as Fas, and resulting in the activation of caspase-8 or -10 17 (a third general pathway, originating from the endoplasmic reticulum and resulting in the activation of caspase-12 and -9, has also recently been described). [18][19][20][21][22] Much less is known about the biochemical mediators of type 2 and type 3 cell death. Type 2 (autophagic) cell death can be activated in some cases by Ras, 23 while the molecular activation of type 3 cell death is unknown.…”

Section: Introductionmentioning

confidence: 99%

Paraptosis: mediation by MAP kinases and inhibition by AIP-1/Alix

et al. 2004

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Programmed cell death (pcd) may take the form of apoptotic or nonapoptotic pcd. Whereas cysteine aspartyl-specific proteases (caspases) mediate apoptosis, the mediators of nonapoptotic cell death programs are much less well characterized. Here, we report that paraptosis, an alternative, nonapoptotic cell death program that may be induced by the insulin-like growth factor I receptor (among other inducers), is mediated by mitogen-activated protein kinases (MAPKs) and inhibited by AIP-1/Alix. The inhibition by AIP-1/Alix is specific for paraptosis since apoptosis was not inhibited. Caspases were not activated in this paradigm, nor were caspase inhibitors effective in blocking cell death. However, insulinlike growth factor I receptor (IGFIR)-induced paraptosis was inhibited by MEK-2-specific inhibitors and by antisense oligonucleotides directed against c-jun N-terminal kinase-1 (JNK-1). These results suggest that IGFIR-induced paraptosis is mediated by MAPKs, and inhibited by AIP-1/Alix.

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Coupling endoplasmic reticulum stress to the cell death program: role of the ER chaperone GRP78

Cited by 533 publications

References 41 publications

Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease

Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease

Acidosis Causes Endoplasmic Reticulum Stress and Caspase-12-Mediated Astrocyte Death

Paraptosis: mediation by MAP kinases and inhibition by AIP-1/Alix

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