Ero1α requires oxidizing and normoxic conditions to localize to the mitochondria-associated membrane (MAM)

Gilady, Susanna Y.; Bui, Michael; Lynes, Emily M.; Benson, Matthew D.; Watts, Russell; Vance, Jean E.; Simmen, Thomas

doi:10.1007/s12192-010-0174-1

Cited by 159 publications

(118 citation statements)

References 51 publications

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“…3B) Simmen et al 2010). On the MAM, ER chaperones (CNX, BiP), oxidoreductases (ERp44, Ero1a), and Ca 2þ channels/pumps (IP3R3, SERCA2b, and Sig-1R) are enriched, thereby creating an ideal environment for oxidative protein folding, as well as the regulation of Ca 2þ flux (Gilady et al 2010). On the MAM, IP3Rs, SERCA2b, and Sig-1R are regulated by ER oxidoreductases and/or chaperones, and ROS are produced as a by-product of oxidative protein folding.…”

Section: Specialized Compartments Within the Ermentioning

confidence: 99%

Protein Folding and Quality Control in the ER

Araki

Nagata

2011

Cold Spring Harbor Perspectives in Biology

326

285

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The endoplasmic reticulum (ER) uses an elaborate surveillance system called the ER quality control (ERQC) system. The ERQC facilitates folding and modification of secretory and membrane proteins and eliminates terminally misfolded polypeptides through ER-associated degradation (ERAD) or autophagic degradation. This mechanism of ER protein surveillance is closely linked to redox and calcium homeostasis in the ER, whose balance is presumed to be regulated by a specific cellular compartment. The potential to modulate proteostasis and metabolism with chemical compounds or targeted siRNAs may offer an ideal option for the treatment of disease.

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Section: Specialized Compartments Within the Ermentioning

confidence: 99%

Protein Folding and Quality Control in the ER

Araki

Nagata

2011

Cold Spring Harbor Perspectives in Biology

326

285

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“…The dispensability of PERK kinase activity for ERmitochondria tethering appears to exclude the possibility that the observed effects might be secondary to the induction of other MAM components like ERO1a 31,32 and the truncated variant of the SERCA pump (S1T) 33 by the PERK-ATF4/ CHOP pathway.…”

Section: Discussionmentioning

confidence: 99%

PERK is required at the ER-mitochondrial contact sites to convey apoptosis after ROS-based ER stress

et al. 2012

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Endoplasmic reticulum stress is emerging as an important modulator of different pathologies and as a mechanism contributing to cancer cell death in response to therapeutic agents. In several instances, oxidative stress and the onset of endoplasmic reticulum (ER) stress occur together; yet, the molecular events linking reactive oxygen species (ROS) to ER stress-mediated apoptosis are currently unknown. Here, we show that PERK (RNA-dependent protein kinase (PKR)-like ER kinase), a key ER stress sensor of the unfolded protein response, is uniquely enriched at the mitochondria-associated ER membranes (MAMs). PERK À / À cells display disturbed ER morphology and Ca 2 þ signaling as well as significantly weaker ER-mitochondria contact sites. Re-expression of a kinase-dead PERK mutant but not the cytoplasmic deletion mutant of PERK in PERK À / À cells re-establishes ER-mitochondria juxtapositions and mitochondrial sensitization to ROS-mediated stress. In contrast to the canonical ER stressor thapsigargin, during ROS-mediated ER stress, PERK contributes to apoptosis twofold by sustaining the levels of pro-apoptotic C/EBP homologous protein (CHOP) and by facilitating the propagation of ROS signals between the ER and mitochondria through its tethering function. Hence, this study reveals an unprecedented role of PERK as a MAMs component required to maintain the ER-mitochondria juxtapositions and propel ROS-mediated mitochondrial apoptosis. Furthermore, it suggests that loss of PERK may cause defects in cell death sensitivity in pathological conditions linked to ROS-mediated ER stress. Cell Death and Differentiation (2012) 19, 1880-1891 doi:10.1038/cdd.2012; published online 15 June 2012The endoplasmic reticulum (ER) constitutes a specialized organelle involved in crucial cellular functions, including protein folding and Ca 2 þ storage/signaling. Alterations in the ER folding environment cause the accumulation of misfolded proteins in the ER lumen, leading to ER stress.

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“…HeLa cells were treated with tunicamycin (10 mM) or thapsigargin (1.5 mM) for 4 h, and immunofluorescence microscopy was performed using the indicated primary antibodies, according to the protocol described previously (Gilady et al, 2010). LDLR surface binding was detected by binding of a 1:100 dilution of anti-LDLR antibody in DMEM, 10% FBS and 1% BSA.…”

Section: Immunofluorescence Microscopymentioning

confidence: 99%

Palmitoylation is the Switch that Assigns Calnexin to Quality Control or ER Calcium Signaling

Lynes

Raturi

Shenkman

et al. 2013

Journal of Cell Science

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136

111

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SummaryThe palmitoylation of calnexin serves to enrich calnexin on the mitochondria-associated membrane (MAM). Given a lack of information on the significance of this finding, we have investigated how this endoplasmic reticulum (ER)-internal sorting signal affects the functions of calnexin. Our results demonstrate that palmitoylated calnexin interacts with sarcoendoplasmic reticulum (SR) Ca 2+ transport ATPase (SERCA) 2b and that this interaction determines ER Ca 2+ content and the regulation of ER-mitochondria Ca 2+ crosstalk. In contrast, non-palmitoylated calnexin interacts with the oxidoreductase ERp57 and performs its well-known function in quality control. Interestingly, our results also show that calnexin palmitoylation is an ER-stress-dependent mechanism. Following a short-term ER stress, calnexin quickly becomes less palmitoylated, which shifts its function from the regulation of Ca 2+ signaling towards chaperoning and quality control of known substrates. These changes also correlate with a preferential distribution of calnexin to the MAM under resting conditions, or the rough ER and ER quality control compartment (ERQC) following ER stress. Our results have therefore identified the switch that assigns calnexin either to Ca 2+ signaling or to protein chaperoning.

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Ero1α requires oxidizing and normoxic conditions to localize to the mitochondria-associated membrane (MAM)

Cited by 159 publications

References 51 publications

Protein Folding and Quality Control in the ER

Protein Folding and Quality Control in the ER

PERK is required at the ER-mitochondrial contact sites to convey apoptosis after ROS-based ER stress

Palmitoylation is the Switch that Assigns Calnexin to Quality Control or ER Calcium Signaling

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