Expression of citrate carrier gene is activated by ER stress effectors XBP1 and ATF6α, binding to an UPRE in its promoter

doi:10.1016/j.bbagrm.2014.10.004

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms

Volume 1849, Issue 1, January 2015, Pages 23-31

https://doi.org/10.1016/j.bbagrm.2014.10.004 Get rights and content

Highlights

•
Expression of CiC is activated in cells during ER stress induced by tunicamycin.
•
A functional Unfolded Protein Response Element has been found in CiC promoter.
•
ER stress activation of CiC is under the ATF6α and XBP1 branches of UPR pathway.
•
Increase of ER proteins acetylation upon ER stress is dependent on the CiC expression.

Abstract

The Unfolded Protein Response (UPR) is an intracellular signaling pathway which is activated when unfolded or misfolded proteins accumulate in the Endoplasmic Reticulum (ER), a condition commonly referred to as ER stress. It has been shown that lipid biosynthesis is increased in ER-stressed cells. The N^ε-lysine acetylation of ER-resident proteins, including chaperones and enzymes involved in the post-translational protein modification and folding, occurs upon UPR activation. In both ER proteins acetylation and lipid synthesis, acetyl-CoA is the donor of acetyl group and it is transported from the cytosol into the ER. The cytosolic pool of acetyl-CoA is mainly derived from the activity of mitochondrial citrate carrier (CiC). Here, we have demonstrated that expression of CiC is activated in human HepG2 and rat BRL-3A cells during tunicamycin-induced ER stress. This occurs through the involvement of an ER stress responsive region identified within the human and rat CiC proximal promoter. A functional Unfolded Protein Response Element (UPRE) confers responsiveness to the promoter activation by UPR transducers ATF6α and XBP1. Overall, our data demonstrate that CiC expression is activated during ER stress through the binding of ATF6α and XBP1 to an UPRE element located in the proximal promoter of Cic gene. The role of ER stress-mediated induction of CiC expression has been discussed.

Introduction

An essential function of the Endoplasmic Reticulum (ER) is to ensure the correct folding of proteins residing within and transiting along the secretory pathway [1], [2]. When the ER protein-folding capacity falls, a condition of ER-stress is established and leads to the activation of an evolutionarily conserved Unfolded Protein Response (UPR) signaling pathway in order to restore the ER homeostasis [3], [4].

In mammalian cells, UPR signaling pathway consists of three main branches carried out by the UPR transducers Inositol Requiring Protein-1/X-box-Binding Protein-1 (IRE1/XBP1), the Activating Transcription Factor-6 (ATF6), and the Protein Kinase RNA (PKR)-like ER Kinase (PERK), respectively. IRE1, ATF6 and PERK are transmembrane ER proteins, with their N-terminus located in the lumen of the ER and the C-terminus in the cytosol [3], [4]. Both IRE1 and PERK contain an unfolded protein-sensing domain in their N-terminus. In the direct recognition model of UPR activation, accumulating unfolded proteins directly interact with the lumenal domain of IRE1 and PERK, causing their oligomerization-induced activation. In the alternative indirect recognition model, the ER resident chaperone 78-kDa Glucose-Regulated Protein (GRP78, also known as immunoglobulin heavy chain binding protein, BiP) binds the N-terminus of IRE1, ATF6 and PERK, preventing their activation under normal conditions. When ER stress occurs, GRP78 binds unfolded proteins and releases IRE1, PERK, and ATF6, allowing them to transduce the UPR signal [5], [6], [7], [8], [9].

Disruption of ER homeostasis and the consequent activation of UPR have been observed in the liver and adipose tissue of humans with nonalcoholic fatty liver disease (NAFLD) and/or obesity [10]. NAFLD is characterized by fatty infiltration (steatosis) of the liver in the absence of chronic alcohol consumption or other liver diseases. Sources of hepatic lipids in NAFLD include dietary chylomicron remnants, free fatty acids released from adipose tissue triglycerides, and the de novo lipogenesis in which acetyl-CoA is converted in fatty acids [10].

UPR activation is also accompanied by an increase of the status of N^ε-lysine acetylation of ER-resident proteins [11], most of them are chaperones and enzymes involved in the post-translational protein modification and folding, including GRP78 [11]. Recent studies reported that inactivation of some histone deacetylases through gene knockdown or treatment with specific inhibitors triggers the hyperacetylation of GRP78 and the activation of the UPR transducers PERK and ATF6 [12], [13]. In the reaction of N^ε-lysine acetylation, the donor of the acetyl group is represented by acetyl-CoA, which is transported from the cytosol to the ER lumen by the membrane transporter SLC33A1/AT-1 [14], [15].

The cytosolic pool of acetyl-CoA is mainly derived from glucose or amino acid metabolism through the shuttle citrate/malate catalyzed by citrate carrier (CiC), also known as tricarboxylate carrier, which transports citrate from the mitochondrion to the cytosol [16].

CiC is an integral protein of the mitochondrial inner membrane, which catalyzes the efflux of citrate in exchange for tricarboxylates, dicarboxylate (malate) or phosphoenolpyruvate from the mitochondrial matrix to the cytosol. Here, by the action of ATP-citrate lyase, citrate provides the carbon units for fatty acids and cholesterol biosynthesis [16]. This carrier plays a pivotal role in intermediary metabolism by connecting carbohydrate with lipid metabolism, supplying to cytosol acetyl-CoA, in the form of citrate.

It has been reported that CiC activity is under hormonal [17], [18] and nutritional control [19], [20], [21], [22]. Structural and functional studies of the rat Cic gene promoter led to the characterization of binding sites for transcription factors such as Sterol Regulatory Element-Binding Protein-1 (SREBP-1) and Peroxisomal Proliferator-Activated Receptors (PPARs), both involved in the control of lipid homeostasis [20], [23]. It has also been shown that transport of citrate (acetyl-CoA) from mitochondria to the cytosol is essential for important functions other than fatty acids and cholesterol syntheses, such as the adipogenesis [20], inflammation response [24], maintaining of chromosomes integrity [25], insulin secretion [26], and cancer [27].

Given the importance of CiC as a key protein in lipogenesis and in aforementioned functions, and due to the poor knowledge about the ER stress-mediated activation of lipogenic gene expression, we investigated the modulation of CiC expression during the ER stress and the molecular mechanism underlying this regulation. To this aim, the characterization of the human and rat Cic gene promoter was carried out in order to locate the putative region involved in the activation of Cic gene expression in response to ER stress. Experiments were performed to demonstrate the activation of CiC promoter through the binding of ATF6α and XBP1 to an Unfolded Protein Response Element (UPRE), upon ER stress induction. Finally, results showed that the acetylation status of ER resident proteins was affected by CiC expression. On the basis of these results, a potential role of CiC activation by ER stress was proposed.

Section snippets

Plasmid and reporter vector construction

Four DNA fragments of human CiC promoter (NCBI accession number BC008061.2), sized from − 819 to + 29, − 413 to + 29, − 144 to + 29, and − 60 to + 29 bp, were obtained by PCR using genomic DNA from HepG2 cells as template and the forward primers hCICfor (− 819) (5′ AAGCTTGGTACCGGTACCGGACCTCATAAAAG-3′), hCICfor (− 413) (5′-AAGCTTGGTACCGCTAGCCCCACGTGTTTTCG-3′), hCICfor (− 144) (5′-AAGCTTGGTACCAGGCCTCAGTTTCCCGGCCC-3′), and hCICfor (− 60) (5′-AAGCTTGGTACCGGCCGCCCCGCCCCTGGGAC-3′). The common reverse primer was

Role of ER stress on CiC expression in HepG2 and BRL-3A cells

To investigate the effect of ER stress on Cic expression, the abundance of CiC mRNA was analyzed by real-time qPCR in human HepG2 and in rat BRL-3A cells, both cultured without (control) or with 1 μg/ml tunicamycin. Quantitation of CiC mRNA abundance showed that tunicamycin caused a time-dependent increase of Cic gene expression in ER-stressed HepG2 and BRL-3A cells, reaching maximum levels at 24 h and 12 h, respectively (Fig. 1A). The increase of the abundance of CiC mRNA, induced by ER stressor,

Discussion

Citrate carrier has so far been studied mainly as a protein which provides the cytosol of acetyl-CoA, precursor of the de novo fatty acids and cholesterol syntheses. It represents, indeed, the link between the glycolytic and lipogenic pathways [16].

In recent years, new insights are highlighting the role of the citrate carrier in important cellular functions other than lipid synthesis, such as the adipogenesis [20], maintaining of chromosome integrity [25], inflammation response [24], insulin

Funding

The research discussed in the present study was supported by the Ministero dell'Università e Ricerca (MIUR) (MIUR- FUR ex 60%).

Acknowledgements

We thank prof. Kazutoshi Mori (Department of Biophysics, Kyoto University) for providing the pcDNA3–ATF6 (373) and pcDNA3–XBP1s and prof. Bruno Di Jeso (Department of Biological and Environmental and Sciences and Technologies, University of Salento) for providing the antibody against GRP78.

References (43)

R. Benyair et al.
Protein quality control, retention, and degradation at the endoplasmic reticulum
Int. Rev. Cell Mol. Biol.
(2011)
A. Buchberger et al.
Protein quality control in the cytosol and the endoplasmic reticulum: brothers in arms
Mol. Cell
(2010)
J. Shen et al.
ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals
Dev. Cell
(2002)
M. Pehar et al.
Proteomic assessment shows that many endoplasmic reticulum (ER)-resident proteins are targeted by N^ε-lysine acetylation in the lumen of the organelle and predicts broad biological impact
J. Biol. Chem.
(2012)
M. Pehar et al.
SLC33A1/AT1 protein regulates the induction of autophagy downstream of IRE1/XBP1 pathway
J. Biol. Chem.
(2012)
F. Damiano et al.
Streptozotocin-induced diabetes affects in rat liver citrate carrier gene expression by transcriptional and posttranscriptional mechanisms
Int. J. Biochem. Cell Biol.
(2011)
L. Siculella et al.
n-6 PUFAs downregulate expression of the tricarboxylate carrier in rat liver by transcriptional and posttranscriptional mechanisms
J. Lipid Res.
(2004)
F. Damiano et al.
Citrate carrier promoter is target of peroxisome proliferator-activated receptor alpha and gamma in hepatocytes and adipocytes
Int. J. Biochem. Cell Biol.
(2012)
A. Ferramosca et al.
Dietary fat and hepatic lipogenesis: mitochondrial citrate carrier as a sensor of metabolic changes
Adv. Nutr.
(2014)
H. Yoshida et al.
Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors
J. Biol. Chem.
(1998)

H. Yoshida et al.

XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor

Cell

(2001)

K. Yamamoto et al.

Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6 and XBP1

Dev. Cell

(2007)

Y. Wang et al.

Activation of ATF6 and an ATF6 DNA binding site by the endoplasmic reticulum stress response

J. Biol. Chem.

(2000)

H. Yoshida et al.

A time-dependent phase shift in the mammalian unfolded protein response

Dev. Cell

(2003)

R. Sriburi et al.

Coordinate regulation of phospholipid biosynthesis and secretory pathway gene expression in XBP-1(S)-induced endoplasmic reticulum biogenesis

J. Biol. Chem.

(2007)

D.T. Rutkowski et al.

UPR pathways combine to prevent hepatic steatosis caused by ER stress-mediated suppression of transcriptional master regulators

Dev. Cell

(2008)

K. Mori

Signalling pathways in the unfolded protein response: development from yeast to mammals

J. Biochem.

(2009)

S.S. Cao et al.

Targeting endoplasmic reticulum stress in metabolic disease

Expert Opin. Ther. Targets

(2013)

D. Ron et al.

Signal integration in the endoplasmic reticulum unfolded protein response

Nat. Rev. Mol. Cell Biol.

(2007)

B.M. Gardner et al.

Unfolded proteins are Ire1-activating ligands that directly induce the unfolded protein response

Science

(2011)

A. Bertolotti et al.

Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response

Nat. Cell Biol.

(2000)

Cited by (25)

Evaluation of aminopyrrolidine amide to improve chloride transport in CFTR-defective cells
2022, Bioorganic and Medicinal Chemistry Letters
Citation Excerpt :
We treated cells with PF-429242 and we observed that the function of the p.Phe508del-CFTR Cl- channel was increased in link with its significantly increased expression (mRNA and protein). The active form of ATF6 links the promoters of UPR target genes inducing the transcription of ER chaperones, proteins of the quality control of the ER and of the ER-associated degradation.45–46,49–51 Therefore, it was possible that the observed effects upon P.Phe508del-CFTR were due to the modulation of the expression of ATF6-depedent genes.
The aminopyrrolidine amide PF-429242 is a specific inhibitor of the Site-1 Protease which is responsible for the cleavage, and thus the activation of the Activating Transcription Factor 6 that down regulates many genes, during the Unfolded Protein Response. We hypothesized that PF-429242 could be used to prevent the ATF6-dependent down regulation of some genes. We chose the CFTR gene encoding the CFTR chloride channel as a model because it is down-regulated by ATF6 in Cystic Fibrosis. We evaluated the action of PF-429242 in human bronchial cells expressing the most frequent mutation of CFTR (p.Phe508del) found in patients. We observed that PF-429242 increases the synthesis of the mRNA and the protein encoded by the CFTR gene harbouring the mutation. We also observed that PF-429242 alleviates the defects of the p.Phe508del-CFTR channel in human Cystic Fibrosis cells. Our results suggest that aminopyrrolidine amide is a potential therapeutic target for Cystic Fibrosis that could also have beneficial effects in other diseases involving CFTR, such as the Chronic Obstructive Pulmonary Disease.
Melatonin attenuates spatial learning and memory dysfunction in developing rats by suppressing isoflurane-induced endoplasmic reticulum stress via the SIRT1/Mfn2/PERK signaling pathway
2022, Heliyon
Citation Excerpt :
CHOP is a member of the CCAAT/enhancer binding protein family, and changes in CHOP expression directly affect the balance between proapoptotic and antiapoptotic signals [37]. The upregulation and downregulation of CHOP expression results in the activation of proapoptotic and antiapoptotic proteins, respectively [38, 39, 40]. During ER stress, caspase 12 activation is also a proapoptotic signal and is involved in neuronal apoptosis in neurodegenerative diseases [37].
Use of the inhalation anesthetic isoflurane may increase the risk of cognitive deficiency and neurotoxicity after birth. A growing body of evidence suggests that melatonin is an effective treatment for various types of oxidative stress damage and neurodegenerative disease. In this study, we aimed to examine the effects of melatonin on isoflurane-induced endoplasmic reticulum (ER) stress, spatial learning and memory impairment during development. The rats were grouped according to whether the rats were exposed to isoflurane or a control gas and whether they were administered melatonin or phosphate buffered saline (PBS). We administered isoflurane to 7-day-old Sprague–Dawley rat pups with intraperitoneal injections of melatonin (20 mg/kg) 15 min before and 3 h after the initiation of anesthesia. Twelve hours after isoflurane anesthesia, rats were randomly selected from each group and sacrificed. The hippocampal tissue and serum were collected to determine the levels of SIRT1, Mfn2, PERK, and other proteins or cytokines related to ER stress, apoptosis, and neuroinflammation. Subsequently, all remaining rats were assessed for spatial learning and memory deficiency 31 days after birth using the Morris water maze test. We found that melatonin attenuated isoflurane-induced ER stress and neuroapoptosis in the hippocampus and decreased the level of neuroinflammatory markers in the serum of newborn rats, resulting in improved spatial learning and memory. In addition, the neuroprotective effect of melatonin was weakened after the SIRT1/Mfn2/PERK signaling pathway was suppressed by lentivirus transfection. Therefore, our findings demonstrate that melatonin ameliorates spatial learning and memory impairment after isoflurane exposure, and these beneficial effects are associated with a reduction in ER stress, neuroapoptosis, and neuroinflammation via the SIRT1/Mfn2/PERK signaling pathway.
HSF1-SELENOS pathway mediated dietary inorganic Se-induced lipogenesis via the up-regulation of PPARγ expression in yellow catfish
2022, Biochimica et Biophysica Acta - Gene Regulatory Mechanisms
Citation Excerpt :
The SELENOS knockdown led to the inhibition of adipogenesis and reduction of TGs content via the inositol-requiring enzyme 1α (IRE1α)-mediated X-box binding protein 1 (XBP1) pathway [13]. The glucose-regulated protein 78 (GRP78) and calreticulin (CALR), two important ER-resident chaperones, were considered to be the markers for ER stress [16]. ER stress will in turn activate the unfolded protein response (UPR) [17], which induces the activation of three pathways: IRE1α-XBP1, PERK-eIF2α-ATF4, and transcription factor 6α (ATF6α) [16,17].
At present, studies involved in the effects of dietary Se sources on lipid metabolism were very scarce and the underlying mechanism remains unknown. Previous studies reported that dietary Se sources differentially affected selenoprotein S (SELENOS) expression and SELENOS affected lipid metabolism via the inositol-requiring enzyme 1α (IRE1α)- spliced X-box binding protein 1 (XBP1s) pathway. Thus, we used yellow catfish as an experimental model to explore whether dietary selenium sources affected the hepatic lipid metabolism, and further determined the role of SELENOS-IRE1α-XBP1s pathway in dietary selenium sources affecting hepatic lipid metabolism. Compared with the selenomethionine (S-M) group, sodium selenite (SS) group possessed higher liver triglycerides (TGs) (34.7%), lipogenic enzyme activities (57.9–70.6%), and lower antioxidant enzyme activities (23.3–35.5%), increased protein levels of heat shock transcription factor 1 (HSF1) and SELENOS (1.17-fold and 47.4%, respectively), and XBP1s- peroxisome proliferators-activated receptor γ (PPARγ) pathway. Blocking SELENOS and PPARγ by RNA interference demonstrated that the SELENOS/XBP1s/PPARγ axis was critical for S-S-induced lipid accumulation. Moreover, S-S-induced upregulation of SELENOS was via the increased DNA binding capacity of HSF1 to SELENOS promoter, which activated the XBP1s/PPARγ pathway and promoted lipogenesis and lipid accumulation. XBP1s is required for S-S-induced upregulation of PPARγ expression. Our finding elucidated the mechanism of dietary Se sources affecting the lipid metabolism in the liver of yellow catfish and demonstrated novel function of SELENOS in metabolic regulation. Our study also suggested that seleno-methionine was a better Se source than selenite against abnormal lipid deposition in the liver of yellow catfish.
Dietary citrate acutely induces insulin resistance and markers of liver inflammation in mice
2021, Journal of Nutritional Biochemistry
Citrate is widely used as a food additive being part of virtually all processed foods. Although considered inert by most of the regulatory agencies in the world, plasma citrate has been proposed to play immunometabolic functions in multiple tissues through altering a plethora of cellular pathways. Here, we used a short-term alimentary intervention (24 hours) with standard chow supplemented with citrate in amount corresponding to that found in processed foods to evaluate its effects on glucose homeostasis and liver physiology in C57BL/6J mice. Animals supplemented with dietary citrate showed glucose intolerance and insulin resistance as revealed by glucose and insulin tolerance tests. Moreover, animals supplemented with citrate in their food displayed fed and fasted hyperinsulinemia and enhanced insulin secretion during an oral glucose tolerance test. Citrate treatment also amplified glucose-induced insulin secretion in vitro in INS1-E cells. Citrate supplemented animals had increased liver PKCα activity and altered phosphorylation at serine or threonine residues of components of insulin signaling including IRS-1, Akt, GSK-3 and FoxO1. Furthermore, citrate supplementation enhanced the hepatic expression of lipogenic genes suggesting increased de novo lipogenesis, a finding that was reproduced after citrate treatment of hepatic FAO cells. Finally, liver inflammation markers were higher in citrate supplemented animals. Overall, the results demonstrate that dietary citrate supplementation in mice causes hyperinsulinemia and insulin resistance both in vivo and in vitro, and therefore call for a note of caution on the use of citrate as a food additive given its potential role in metabolic dysregulation.
Advances into Understanding the Vital Role of the Mitochondrial Citrate Carrier (CIC) in Metabolic Diseases
2020, Pharmacological Research
The mitochondrial citrate carrier (CIC) is a nuclear-encoded protein located in the inner mitochondrial membrane. By mediating efflux of citrate from the mitochondria to the cytosol, CIC links mitochondrial central carbon metabolism and cytosolic lipogenesis together. Abnormal activity or expression of CIC was found in cancers, developmental disorders and many other diseases. Recently, the specific inhibitors of CIC were proved to modify basic cellular metabolism, which in turn led to changes in disease course such as reverted steatohepatitis and cancer cell death. CIC is believed to be a key player and may serve as a novel therapeutic target in types of human metabolic diseases. Therefore, in this paper, we integrally described the structure and function of CIC. Then, we gave an overview of CIC related diseases including cancers, congenital diseases, pro-inflammatory effects and some other diseases. At the same time, the potential molecular mechanisms of CIC in the above diseases were illuminated. Finally, we illuminated some emerging areas for future investigation.
An activating transcription factor 6 beta (ATF6β) regulates apoptosis of hemocyte during immune response in Crassostrea gigas
2020, Fish and Shellfish Immunology
The homeostasis of immune cells during immune response is vital for hosts to defend against invaders. Activating transcription factor 6 (ATF6) is an important transcription factor in the unfolded protein response (UPR) to maintaining cellular homeostasis. In the present study, one ATF6 homologue was identified from Pacific oyster Crassostrea gigas (designated as CgATF6β). The full length cDNA of CgATF6β was of 2645 bp with a 1596 bp open reading frame (ORF) encoding a polypeptide of 531 amino acids. The deduced amino acid sequence of CgATF6β was predicted to contain a transmembrane region, a conserved basic leucine zipper (bZIP) domain, a site 1 protease cleavage site, a site 2 protease cleavage site, and a Golgi localization signal. CgATF6β mRNA was constitutively expressed in hemocytes, gill, mantle, gonad, hepatopancreas and labial palp, with a slightly higher expression level in muscle (2.45-fold of that in gill, p < 0.05). After oysters were challenged with Vibrio splendidus, the mRNA expression levels of CgATF6β in hemocytes were significantly up-regulated at 3 h (2.68-fold of that in seawater group, p < 0.01) and peaked at 12 h (3.14-fold of that in seawater group, p < 0.01). The endogenic CgATF6β protein was mainly located in the cytoplasm of oyster hemocytes, and it was significantly transported into the nuclei of hemocytes at 1.5 h after the challenge with V. splendidus. After an injection with CgATF6β dsRNA, the mRNA expression of CgATF6β was knocked down to 0.26-fold of that in dsGFP group (p < 0.01). In CgATF6β dsRNA-injected oysters, the mRNA expressions of glucose-regulated protein 78 (GRP78), calnexin (CNX) and anti-apoptotic B-cell lymphoma-2 (Bcl-2) in hemocytes were significantly decreased at 12 h after V. splendidus challenge, which were 0.65-fold (p < 0.01), 0.54-fold (p < 0.01) and 0.17-fold (p < 0.01) of that in dsGFP-injected oysters, while the apoptotic rate of hemocytes was significantly up-regulated (1.97-fold of that in dsGFP group, p < 0.05). Collectively, these results suggested that CgATF6β was involved in apoptosis inhibition of oyster hemocytes upon V. splendidus challenge by regulating the expression of CgGRP78, CgCNX and CgBcl-2.

View all citing articles on Scopus

View full text

Expression of citrate carrier gene is activated by ER stress effectors XBP1 and ATF6α, binding to an UPRE in its promoter

Highlights

Abstract

Introduction

Section snippets

Plasmid and reporter vector construction

Role of ER stress on CiC expression in HepG2 and BRL-3A cells

Discussion

Funding

Acknowledgements

Int. Rev. Cell Mol. Biol.

Mol. Cell

Dev. Cell

J. Biol. Chem.

J. Biol. Chem.

Int. J. Biochem. Cell Biol.

J. Lipid Res.

Int. J. Biochem. Cell Biol.

Adv. Nutr.

J. Biol. Chem.

Cell

Dev. Cell

J. Biol. Chem.

Dev. Cell

J. Biol. Chem.

Dev. Cell

Signalling pathways in the unfolded protein response: development from yeast to mammals

J. Biochem.

Targeting endoplasmic reticulum stress in metabolic disease

Expert Opin. Ther. Targets

Signal integration in the endoplasmic reticulum unfolded protein response

Nat. Rev. Mol. Cell Biol.

Unfolded proteins are Ire1-activating ligands that directly induce the unfolded protein response

Science

Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response

Nat. Cell Biol.