A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells

Tirasophon, Witoon; Welihinda, Ajith; Kaufman, Randal J.

doi:10.1101/gad.12.12.1812

Cited by 848 publications

(758 citation statements)

References 46 publications

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“…Caspase-12-mediated astrocyte death K Aoyama et al Ire1-a is broadly expressed, whereas Ire1-b is expressed selectively in foregut-derived epithelium (Tirasophon et al, 1998;Wang et al, 1998). Results of the present study demonstrated a dissociation of Ire1-a from GRP-78 after acidosis, suggesting this as a likely mechanism by which the ER stress response is induced by acidosis.…”

Section: Discussionsupporting

confidence: 51%

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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Section: Discussionsupporting

confidence: 51%

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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“…Ire1a is ubiquitously expressed, while Ire1b is detected only in the intestine. 60,61 Like yeast Ire1p, the overexpression of mammalian Ire1a activates the UPR in the absence of any ER stress signal. 60 However, while Ire1p is absolutely required in yeast for initiation of the UPR, cells derived from Ire1a À/À /Ire1b À/À embryos show no obvious UPR defect, demonstrating that compensatory pathways exist.…”

Section: Esr In Mammalsmentioning

confidence: 99%

“…60,61 Like yeast Ire1p, the overexpression of mammalian Ire1a activates the UPR in the absence of any ER stress signal. 60 However, while Ire1p is absolutely required in yeast for initiation of the UPR, cells derived from Ire1a À/À /Ire1b À/À embryos show no obvious UPR defect, demonstrating that compensatory pathways exist. 13 The mammalian X-box-binding protein-1 (XBP-1), a bZIP member of the CREB/ATF family of transcription factors, serves as a functional homolog of yeast Hac1p.…”

Section: Esr In Mammalsmentioning

confidence: 99%

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

2006

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The proper functioning of the endoplasmic reticulum (ER) is critical for numerous aspects of cell physiology. Accordingly, all eukaryotes react rapidly to ER dysfunction through a set of adaptive pathways known collectively as the ER stress response (ESR). Normally, this suite of responses succeeds in restoring ER homeostasis. However, in metazoans, persistent or intense ER stress can also trigger programmed cell death, or apoptosis. ER stress and the apoptotic program coupled to it have been implicated in many important pathologies but the regulation and execution of ER stressinduced apoptosis in mammals remain incompletely understood. Here, we review what is known about the ESR in both yeast and mammals, and highlight recent findings on the mechanism and pathophysiological importance of ER stressinduced apoptosis.

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“…Upon UPR engagement, IRE1 is activated and its endoribonuclease activity causes removal of a 26-nucleotide intron from X-box binding protein 1 (XBP-1) mRNA (Tirasophon et al, 1998). The spliced XBP-1 mRNA is translated into a potent bZIP transcription factor which translocates to the nucleus and acts as a key regulator of ER folding capacity.…”

Section: Er Stress and The Unfolded Protein Response (Upr)mentioning

confidence: 99%