Re-evaluation of the Role of Calcium Homeostasis Endoplasmic Reticulum Protein (CHERP) in Cellular Calcium Signaling

Sequential mannose trimming of N-glycan (Man9GlcNAc2 -> Man8GlcNAc2 -> Man7GlcNAc2) facilitates endoplasmic reticulum-associated degradation of misfolded glycoproteins (gpERAD). Our gene knockout experiments in human HCT116 cells have revealed that EDEM2 is required for the first step. However, it was previously shown that purified EDEM2 exhibited no α1,2-mannosidase activity toward Man9GlcNAc2 in vitro. Here, we found that EDEM2 was stably disulfide-bonded to TXNDC11, an endoplasmic reticulum protein containing five thioredoxin (Trx)-like domains. C558 present outside of the mannosidase homology domain of EDEM2 was linked to C692 in Trx5, which solely contains the CXXC motif in TXNDC11. This covalent bonding was essential for mannose trimming and subsequent gpERAD in HCT116 cells. Furthermore, EDEM2-TXNDC11 complex purified from transfected HCT116 cells converted Man9GlcNAc2 to Man8GlcNAc2(isomerB) in vitro. Our results establish the role of EDEM2 as an initiator of gpERAD, and represent the first clear demonstration of in vitro mannosidase activity of EDEM family proteins.

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Role of cellular calcium homeostasis in toxic liver injury induced by the pyrrolizidine alkaloid senecionine and the alkenaltrans-4-OH-2-hexenal

Journal of Biochemical Toxicology ◽

10.1002/jbt.2570020302 ◽

1987 ◽

Vol 2 (3) ◽

pp. 155-167 ◽

Cited By ~ 20

Author(s):

Donna S. Griffin ◽

H. J. Segall

Keyword(s):

Liver Injury ◽

Calcium Homeostasis ◽

Pyrrolizidine Alkaloid ◽

Cellular Calcium ◽

Toxic Liver Injury

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Activation of MYD116 (gadd34) expression following transient forebrain ischemia of rat: implications for a role of disturbances of endoplasmic reticulum calcium homeostasis

Molecular Brain Research ◽

10.1016/s0169-328x(98)00276-9 ◽

1999 ◽

Vol 63 (2) ◽

pp. 225-232 ◽

Cited By ~ 43

Author(s):

Jens Doutheil ◽

Sonja Althausen ◽

Cornelia Gissel ◽

Wulf Paschen

Keyword(s):

Endoplasmic Reticulum ◽

Calcium Homeostasis ◽

Forebrain Ischemia ◽

Transient Forebrain Ischemia ◽

Endoplasmic Reticulum Calcium

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Dominant Role of Mitochondria in Calcium Homeostasis of Single Rat Pituitary Corticotropes

Endocrinology ◽

10.1210/en.2005-0358 ◽

2005 ◽

Vol 146 (11) ◽

pp. 4985-4993 ◽

Cited By ~ 10

Author(s):

Andy K. Lee ◽

Amy Tse

Keyword(s):

Endoplasmic Reticulum ◽

Plasma Membrane ◽

Patch Clamp ◽

Calcium Homeostasis ◽

Dominant Role ◽

Capacitance Measurement ◽

Rat Pituitary ◽

Combined Actions ◽

Mitochondrial Uncouplers

The rise in cytosolic free Ca2+ concentration ([Ca2+]i) is the major trigger for secretion of ACTH from pituitary corticotropes. To better understand the shaping of the Ca2+ signal in corticotropes, we investigated the mechanisms regulating the depolarization-triggered Ca2+ signal using patch-clamp techniques and indo-1 fluorometry. The rate of cytosolic Ca2+ clearance was unaffected by inhibitors of Na+/Ca2+ exchanger or plasma membrane Ca2+-ATPase (PMCA), slightly slowed by sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitor, but dramatically slowed by mitochondrial uncouplers or inhibitor of mitochondrial uniporter. Measurements with rhod-2 revealed that depolarization-triggered increase in mitochondrial Ca2+ concentration. Thus, mitochondria have a dominant role in cytosolic Ca2+ clearance. Using the Mn2+ quench technique, we found the presence of a continuous basal Ca2+ influx in corticotropes. This basal Ca2+ influx was balanced by the combined actions of mitochondrial uniporter and PMCA and SERCA pumps. Inhibition of the mitochondrial uniporter or PMCA or SERCA pumps elevated basal [Ca2+]i. Using membrane capacitance measurement, we found that the change in the shape of the depolarization-triggered Ca2+ signal after mitochondrial inhibition was associated with enhancement of the exocytotic response. Thus, mitochondria have a dominant role in the regulation of Ca2+ signal and exocytosis in corticotropes.

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The role of MATER in endoplasmic reticulum distribution and calcium homeostasis in mouse oocytes

Developmental Biology ◽

10.1016/j.ydbio.2013.12.025 ◽

2014 ◽

Vol 386 (2) ◽

pp. 331-339 ◽

Cited By ~ 29

Author(s):

Boram Kim ◽

Xuesen Zhang ◽

Rui Kan ◽

Roy Cohen ◽

Chinatsu Mukai ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Calcium Homeostasis ◽

Mouse Oocytes

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Role of cortical endoplasmic reticulum protein Ist2 in Saccharomyces cerevisiae cells during dehydration and subsequent rehydration

10.26226/morressier.5f7d97536934880e60c0a503 ◽

2020 ◽

Author(s):

Edgars Dauss

Keyword(s):

Saccharomyces Cerevisiae ◽

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Protein ◽

Cortical Endoplasmic Reticulum

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Abstract P467: Cardiac-specific Deletion Of Voltage Dependent Anion Channel 2 Leads To Dilated Cardiomyopathy By Altering Calcium Homeostasis

Circulation Research ◽

10.1161/res.129.suppl_1.p467 ◽

2021 ◽

Vol 129 (Suppl_1) ◽

Author(s):

Thirupura S Shankar ◽

Dinesh Kumar Anandamurugan Ramadurai ◽

Kira Steinhorst ◽

Salah Sommakia ◽

Rachit Badolia ◽

...

Keyword(s):

Heart Failure ◽

Dilated Cardiomyopathy ◽

Calcium Signaling ◽

Calcium Homeostasis ◽

Calcium Uptake ◽

Mitochondrial Calcium ◽

Voltage Dependent Anion Channel ◽

Knock Out ◽

Cellular Calcium ◽

Mitochondrial Calcium Uptake

Voltage dependent anion channel 2 (VDAC2) is a mitochondrial outer membrane porin known to play a significant role in apoptosis and calcium signaling. Abnormalities in cellular calcium homeostasis often leads to electrical and contractile dysfunction and can cause dilated cardiomyopathy and heart failure. Previous literature suggests that improving mitochondrial calcium uptake via VDAC2 rescues arrhythmia phenotypes in genetic models of impaired cellular calcium signaling. However, the direct role of VDAC2 in intracellular calcium signaling and cardiac function is not well understood. To elucidate the role of VDAC2 in calcium homeostasis, we generated a cardiac-specific deletion of Vdac2 in mice. Our results indicate that loss of VDAC2 in the myocardium during development causes severe impairment in excitation-contraction coupling by reducing mitochondrial calcium uptake (n=3, p<0.05) and thereby impairing intracellular calcium signaling. VDAC2 knock-out mice showed a significant reduction in RYR-mediated calcium release (F/F 0 ) and rate of calcium uptake by SERCA2a [tau(msec)] compared to control mice (N=3, WT=54, KO=38, p<0.0001 (F/F 0 ) and p<0.05 (tau)). We also observed adverse cardiac remodeling which progressed to severe dilated cardiomyopathy and death (N=6, p<0.0001). Reintroducing VDAC2 in 6-week-old knock-out mice partially rescued the cardiomyopathy phenotype evident from improvement in ejection fraction and fractional shortening (n=3, p<0.05). Improving mitochondrial calcium uptake via VDAC2 using a VDAC2 agonist efsevin, increased cardiac contractile force in a mouse model of pressure-overload induced heart failure (N=8, n=22, p<0.05). In conclusion, our findings demonstrate that VDAC2 plays a crucial role in cardiac function by influencing mitochondrial and cellular calcium signaling. Through this role in cellular calcium dynamics and excitation-contraction coupling VDAC2 emerges as a plausible therapeutic target for heart failure.

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Enhancement of ATRA-induced cell differentiation by inhibition of calcium accumulation into the endoplasmic reticulum: cross-talk between RARα and calcium-dependent signaling

Blood ◽

10.1182/blood-2002-09-2730 ◽

2003 ◽

Vol 101 (8) ◽

pp. 3220-3228 ◽

Cited By ~ 30

Author(s):

Sophie Launay ◽

Maurizio Giannı̀ ◽

Luisa Diomede ◽

Laura M. Machesky ◽

Jocelyne Enouf ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Retinoic Acid ◽

Cell Lines ◽

Calcium Homeostasis ◽

Retinoic Acid Receptor ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Cyclopiazonic Acid ◽

Calcium Mobilization ◽

Induced Differentiation ◽

Cellular Calcium

Abstract Sarco–endoplasmic reticulum calcium ATPase (SERCA) enzymes control calcium-induced cellular activation by accumulating calcium from the cytosol into the endoplasmic reticulum (ER). To better understand the role of SERCA proteins and cellular calcium homeostasis in all-trans retinoic acid (ATRA)–induced differentiation, we investigated the effect of pharmacologic inhibition of SERCA-dependent calcium uptake into the ER on ATRA-induced differentiation of the HL-60 myelogenous and the NB4 promyelocytic cell lines. SERCA inhibitors di-tert-butyl-benzohydroquinone (tBHQ), thapsigargin, and cyclopiazonic acid significantly enhanced the induction of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and CD11b marker expression induced by suboptimal concentrations of ATRA (50 nM) in both cell lines. Analysis of cellular calcium homeostasis revealed that a 60% mobilization of the total SERCA-dependent intracellular calcium pool was necessary to obtain enhancement of ATRA-dependent differentiation by tBHQ. Moreover, after 3 days of ATRA treatment in combination with tBHQ, NB4 cells showed a significantly decreased calcium mobilization compared with treatments with tBHQ or ATRA alone, suggesting that enhanced differentiation and calcium mobilization are causally related. Interestingly, several ATRA-resistant NB4-derived cell lines were partially responsive to the differentiation-inducing effect of the combination of the 2 drugs. In addition, we found that retinoic acid receptor α (RARα) and PML-RARα proteins are protected from ATRA-induced proteolytic degradation by SERCA inhibition, indicating that cellular calcium homeostasis may interact with signaling systems involved in the control of ATRA-dependent transcriptional activity. By linking calcium to ATRA-dependent signaling, our data open new avenues in the understanding of the mechanisms of differentiation-induction therapy of leukemia.

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