Open access peer-reviewed chapter

Cellular Functions of ER Chaperones in Regulating Protein Misfolding and Aggregation: An Emerging Therapeutic Approach for Preeclampsia

Written By

Janaranjani Murugesan, Ajithkumar Balakrishnan, Premkumar Kumpati and Hemamalini Vedagiri

Submitted: October 11th, 2021Reviewed: October 18th, 2021Published: December 26th, 2021

DOI: 10.5772/intechopen.101271

Chapter metrics overview

106 Chapter Downloads

View Full Metrics

Abstract

Proteinuria is one of the hallmarks of preeclampsia (PE) that differentiates other hypertensive disorders of pregnancy. Protein misfolding and aggregation is an emerging pathological condition underlying many chronic metabolic diseases and neurodegenerative diseases. Recent studies indicate protein aggregation as an emerging biomarker of preeclampsia, wherein several proteins are aggregated and dysregulated in the body fluids of preeclamptic women, provoking the multi-systemic clinical manifestations of the disease. At the cellular level, these misfolded and aggregated proteins are potentially toxic interfering with the normal physiological process, eliciting the unfolded protein response (UPR) pathway activators in the endoplasmic reticulum (ER) that subsequently augments the ER quality control systems to remove these aberrant proteins. ER resident chaperones, folding enzymes and other proteins serve as part of the ER quality control machinery in restoring nascent protein folding. These ER chaperones are crucial for ER function aiding in native protein folding, maintaining calcium homeostasis, as sensors of ER stress and also as immune modulators. Consequently, ER chaperones seems to be involved in many cellular processes, yet the association is expanding to be explored. Understanding the role and mechanism of ER chaperones in regulating protein misfolding and aggregation would provide new avenues for therapeutic intervention as well as for the development of new diagnostic approaches.

Keywords

  • ER stress
  • ER chaperone
  • protein misfolding
  • aggregation
  • preeclampsia

1. Introduction

Hypertensive disorders are a most common medical problem encountered during pregnancy, affecting 6–8% of all pregnancies. Approximately 70% of hypertensive disorders in pregnancy are mainly due to gestational hypertension, adding up further complications. Preeclampsia (PE) is a multi-systemic disease diagnosed by the presence of new onset hypertension accompanied by proteinuria, renal insufficiency, pulmonary edema, liver failure, neurological complications and fetal growth restriction [1]. The progression of the disease is unpredictable mainly leading to fetal damage associated with other clinical manifestations such as thrombocytopenia, oxidative stress, vascular endothelial dysfunction, systemic inflammation and aberrant angiogenesis, which invariably necessitates early diagnosis of the disease condition so as to prevent further pathogenesis [2].

Proteinuria is one of the hallmarks of preeclampsia that differentiates it from other hypertensive disorders of pregnancy. Recent studies have indicated that protein aggregation as an emerging biomarker of PE, providing insights for therapeutic intervention and development of new diagnostic approaches. Notably, endoplasmic reticulum (ER) stress has recently emerged as a major pathological condition underlying chronic metabolic diseases such as diabetes, cancer, neurodegenerative diseases including PE. At the cellular level, misfolded proteins in the ER significantly lead to ER stress by activating the unfolded protein response (UPR) pathway and molecular chaperones [3, 4, 5, 6, 7, 8]. Mis-folded or aggregated proteins are potentially cytotoxic, and consequently cells possess quality control systems to remove these aberrant proteins. These aberrant proteins will expose hydrophobic regions, free cysteines and tend to aggregate, molecular chaperones play key roles in ER quality control because they recognize mis-folded and aggregation-prone proteins [9, 10]. ER chaperones, folding enzymes and other proteins involved in ER stress would serve as a valuable tool in the investigation of disease pathogenesis, prediction of early diagnostic markers and development of targeted therapies. Hence, exploring the structure and functions of ER chaperones would provide new insights in reducing the cellular stress underlying preeclampsia.

Advertisement

2. Regulation of ER stress

Endoplasmic reticulum (ER) is a cellular organelle involved in multiple cellular processes required for cell survival and physiological functions. These processes include intracellular calcium homeostasis, protein secretion and lipid biosynthesis [11, 12, 13]. ER constantly monitors the level and conformational status of secreted and membrane-related proteins and rapidly activates multiple signaling pathways in response to changes in the quality and quantity of the proteins it processes, levels of reactive oxygen species and metabolic changes. The ER has a specialized environment, including complexes of chaperones and foldases, as well as high fidelity quality controlling mechanisms to ensure the crucial maintenance of ER homeostasis in cells. ER homeostasis is a unique equilibrium between the cellular demand for protein synthesis and the ER folding capacity to promote protein transportation and maturation.

The ER lumen is a one-of-a-kind biological environment, wherein cells are flooded with calcium inorder to mediate the active transport of proteins by calcium ATPases. In addition, ER is also concentrated in calcium-dependent chaperones such as glucose-regulated protein, 78 kDa (GRP78), GRP94 and calreticulin, which help in stabilizing protein-folding intermediates. The oxidative environment in the ER lumen is crucial for disulphide bond formation mediated by protein disulphide isomerase (PDI). The di-sulfide bond formation helps in the proper folding of many proteins intended for secretion as well as those expressed on the cell surface. Different post-translational modifications, including glycosylation and lipidation of proteins too occur in the ER [14, 15].

Disparity in ER function leads to a state known as ER stress, which activates a series of evolutionarily conserved signaling pathways collectively referred to as the unfolded protein response (UPR). Triggering of UPR pathways results in three effector functions: adaptation, alarm and apoptosis [16]. Initially the UPR pathway intends to recover the homeostasis and normalize the ER function. The adaptive mechanism is primarily involved in the activation of transcriptional pathways responsible for enhancing the protein folding capacity and ER-assisted degradation (ERAD). Both of these pathways reduce the load of misfolded proteins in ER by refolding the proteins or exporting them to cytosol for degradation. Initial to this, translation of mRNA is inhibited to prevent the entry of the new protein into ER until the activation of genes encoding UPR pathways [17].

Advertisement

3. Unfolded protein response pathway

Accumulation of unfolded proteins trigger an evolutionarily conserved signaling pathway designated as UPR [18, 19]. Three major proteins: inositol requiring enzyme 1α/β (IRE1), PKR-like ER kinase (PERK), and activating transcription factor 6α/β (ATF6) are the key UPR signaling activators [20, 21, 22]. These activators are capable of retrotrafficking from ER membrane to cytosol by their unique domain organization. They contain 3 domains: an ER luminal domain (LD), a membrane spanning domain and a cytosolic domain. The LD, either directly or indirectly involved in sensing the misfolded proteins [23]. Type 1 transmembrane proteins PERK and IRE1α possess the domain structure that is similar as ER luminal domain structures and a cytosolic Ser/Thr kinase domain, whereas type II transmembrane protein ATF6α contains a cytosolic cyclic AMP response element-binding protein (CREB)-ATF basic leucine zipper domain. UPR pathway activation involves a reduction in protein synthesis, increased protein folding and transport in the ER, an increase in ER-associated protein degradation and autophagy.

After ER is loaded with unfolded proteins, UPR signaling pathways are not simultaneously activated. Primarily ATF6α and IRE1α activation occurs, with subsequent activation of PERK during chronic ER stress [5, 6]. ATF6α and IRE1α are responsible for the activation of transcriptional pathways that increases the cell’s capacity for protein folding, transport and degradation. Adaptive response to the protein misfolding is achieved by ATF6α, which is synthesized as an inactive precursor. The N-terminus is located in cytoplasm and serve as an effector portion which possess DNA-binding and transcriptional activation regions. On the accumulation of unfolded protein in ER, ATF6α travels to the Golgi, and the N-terminal effector portion present in cytosol-bZIP transcription factor is fragmented by S1P and S2P [24]. The fragment induces the genes encoding protein chaperones such as binding immunoglobulin protein (BiP), ER protein 57 (ERp57) and glucose-regulated protein 94 (GRP94), proteins involved in ERAD pathway.

X-box binding protein 1 (XBP1), a transcription factor regulating UPR-associated genes is activated by IRE1 [25, 26]. IRE1 acts as an endonuclease and selectively cleaves the 26-nucleotides from the XBP1u mRNA producing XBP1 spliced mRNA (XBP1s). Activated XBP1s enhances the expression of ER chaperone GRP78, increases the phospholipid biosynthesis and also promotes degradation pathways. Regulated IRE1-dependent decay (RIDD) is also mediated by the activation of IRE1α when the ER protein-folding load is intolerable [27, 28, 29]. PERK-eIF2α-ATF4 mediated pathway attenuates the non-essential protein synthesis and increases the antioxidant defense system. PERK phosphorylates eIF2α at Ser51 which temporarily stops the initiation of global mRNA translation. In irony, phosphorylated eIF2α upregulates the translation of mRNA’s such as ATF4 to increase the protein transport capacity in the ER [30]. Genes encoding ER chaperone protein, folding enzymes and genes encoding ERAD system are activated by p-eIF2α. The collective activation of the genes leads to revive the ER homeostasis and at saturation, the misfolded proteins are degraded by ERAD system assisted by proteasome mediated degradation and pro-apoptotic protein C/EBP homologous protein (CHOP) [31, 32]. Aforementioned pathways are activated based on the severity of the stress condition (Figure 1) [18, 33].

Figure 1.

ER chaperones mediate Protein folding, Quality control, and signaling during ER Stress.

Advertisement

4. Protein misfolding and aggregation

Protein misfolding, aggregation and tissue deposition of fibrous protein aggregates are the critical etiological manifestations of many neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, etc. Recent studies report that numerous aggregated proteins considerably contributes to the heterogeneous clinical manifestations in preeclamptic women, indicating that protein aggregation and misfolding does have a correlation with the disease pathogenesis. Numerous proteomic profiling studies of urine, serum and placental samples from preeclamptic women based on MS analysis, has revealed that aggregation of proteins significantly contributes to the PE associated pathogenesis. Several proteins, including amyloid beta peptide, transthyretin, alpha-1 antitrypsin, albumin, IgG k-free light chains, and ceruloplasmin are aggregated in PE, resulting in toxic deposition of amyloid-like aggregates in the placenta and body fluids [34, 35]. In addition, many extracellular chaperones like casein, clusterin, pregnancy zone protein are implicated to be dysregulated in pregnancy, leading to the accumulation of misfolded proteins and disease manifestation. Probably, these aggregated proteins in the early stages of pregnancy induces defective trophoblast invasion, placental ischemia, ER stress thereby promoting PE manifestation. Insights into the molecular mechanisms of formation of these aggregated proteins and understanding the role of molecular chaperones in regulating the misfolded proteins will open new avenues for pharmacological intervention and therapeutic targeting of PE.

Disruption of ER homeostasis as a result of excess accumulation of unfolded/misfolded proteins due to prolonged or severe ER stress is involved in several pathologies that induce endometriosis and endometrial/ovarian cancers as well as various pregnancy complications that result in preeclampsia, fetal growth restriction and preterm birth. Depending on the severity of ER stress, UPR behaves as sort of binary switch between life and death. Initially, the UPR aims to restore ER homeostasis, but if these attempts fail then the apoptotic cascade is activated. These pathways are now recognized as playing a central role in the pathophysiology of chronic diseases, which contributes to the placental pathology in early-onset PE [36].

The ER has tremendous intracellular store of Ca2+ necessary for regulating a variety of cellular functions both in the ER lumen and cytosol. Inside the ER lumen, huge reserves of Ca2+ are important for proper protein folding assisting disulfide bond forming chaperone, protein disulfide isomerases (PDI). To maintain the ER calcium levels, sarcoendoplasmic reticulum calcium transport ATPase (SERCA) pumps in the ER membrane actively transport Ca2+ from the cytosol into the ER lumen. These pumps are specifically regulated based on the proportion of Ca2+ in the ER lumen to the cytosol. Alteration in SERCA pumps blocks the movement of Ca2+ into the ER, decreasing the function of molecular chaperones and PDI, thereby increasing the burden of misfolded proteins in the ER [37].

Advertisement

5. Pathophysiology of PE

Impaired placentation mainly contributes to the manifestation of systemic symptoms in PE, which may be preceded or followed by protein misfolding and aggregation along with subsequent placental release of inflammatory cytokines, anti-angiogenetic factors, placental debris and particles as well as protein aggregates into the maternal circulation. This pre-clinical dysregulation causes endothelial dysfunction, excessive thrombin generation, systemic inflammation and as a result, elicits multiorgan syndromes of PE [38, 39, 40, 41]. During early stages of pregnancy, several proteins such as transthyretin, may be transported to the placenta from maternal circulation. These aggregation-prone proteins easily undergo misfolding and aggregation in the microenvironment of non-compatible conditions, such as acidic pH, ischemia/hypoxia, amino acid fluctuation, inflammation, and hormonal dysregulation [10, 42]. Protein aggregates induce ER stress and may eventually overwhelm the capacity of the unfolded protein response (UPR) and clearance machineries, leading to deposition and accumulation of these aggregates in trophoblasts, extracellular domains and subsequently causing placental toxicity, poor trophoblast invasion, differentiation, superficial endometrial invasion and failure of spiral artery remodeling. Continuous accumulation of protein aggregates may aggravate ER stress and cause cell apoptosis, leading to release of aggregates into maternal circulation and excretion through injured glomerulus into urine.

ER stress is intricately linked to oxidative stress and inflammation, indicating the co-existence of these pathways in major pathologies particularly early on-set PE, through feed-forward mechanisms [43]. ER stress induction and UPR activation was insignificantly evident in both intra uterine growth retardation (IUGR) and IUGR associated early-onset pre-eclampsia (IUGR + PE) placentas. However, increased apoptosis, higher levels of eIF2α phosphorylation, GRP94 and CHOP in the syncytiotrophoblast and endothelial cells of the foetal capillaries was evident in IUGR + PE placental samples and not in IUGR alone [44]. ER stress associated proteins such as GRP78, GRP94, p-PERK, eIF2α, p-eIF2α, XBP1, CHOP, IRE1, p-IRE1 and inducible nitric oxide synthase (NOS) expression where high in preeclamptic placentas compared to control placenta [45]. Overexpression of placental UPR pathways including IRE1, ATF6 and XBP-1 was significantly observed in early-onset PE compared to that of late-onset of PE and normotensive controls [33]. Preeclamptic placentas feature higher levels of ER stress with prominent activation of pro-inflammatory pathways that contributes to maternal endothelial cell activation. These complexity of cellular responses to ER stress emphasizes the need for a holistic approach for designing potential therapeutic interventions for PE. Antioxidants, ER chaperones, NO donors, statins and H2S donors display pleitropic antioxidant, anti-inflammatory, and pro-angiogenic effects on the signaling pathways involved in the pathophysiology of PE, exhibiting potential strategies for therapeutic intervention [46].

Advertisement

6. ER chaperones

The transcriptional up-regulation of ER chaperones is the hallmark of the ER stress response and occurs in all eukaryotic organisms. The primary function of ER resident chaperones and their cofactors involved in the ER quality control system is to monitor the error-prone steps in protein synthesis and assembly [13, 47]. Three major chaperone families exist in the ER that interact with a wide variety of clients: the lectin chaperones, which generally recognize incompletely folded glycosylated proteins, the heat shock proteins (HSPs) family, which interacts with both nonglycosylated as well as glycosylated proteins and the thiol oxireductases, that aids in the disulphide bond formation [48].

6.1 Heat shock proteins (HSPs)

HSPs are a large family of evolutionarily conserved molecular chaperones, first observed as a group of proteins upregulated in heat-stressed Drosophila melanogaster[49], that are well-known for their roles in protein maturation, re-folding and degradation. These molecular chaperones of this HSP family are critical effectors of the UPR adaptive response. They protect intracellular proteins from misfolding or aggregation, inhibit cell death signaling range and preserve the intracellular signaling pathways that are essential for cell survival. HSPs classified according to their molecular weight as proteins of approximately 84 and 70 kDa (HSP84 and HSP70), are amongst the most prominent chaperones in the ER [50]. HSPs are constitutively expressed, inducibly regulated to prevent aggregation of misfolded polypeptides and assists in refolding, besides being crucial modulators of neurotoxicity in Alzheimer’s disease [51]. Placental ischemia, oxidative stress, maternal systemic inflammatory response are major elements in the pathogenesis of PE that induces the expression of HSP70 which in-turn is associated with cytokine aggravation, oxidative stress and hepatocellular injury [52].

Binding immunoglobulin protein (BiP)/glucose-regulated protein 78 (GRP78), belongs to the HSP70 family, is a well known ER chaperone that binds to the hydrophobic region of unfolded proteins. GRP78 binds through substrate-binding domain and assists protein folding through a conformational change, achieved through the hydrolysis of ATP by the ATPase domain. Another chaperone, oxygen-regulated protein (ORP)150/GRP170 belonging to the HSP110 family (a HSP70 subfamily), assists the protein folding similar to that of BiP. The group of ER DnaJ proteins-ERdj1, ERdj3/HEDJ, ERdj4, ERdj5, SEC63 and p58IPK belonging to the HSP40 family acts as co-chaperones, mediating the acitivity of BiP by regulating its ATPase activity [53, 54].

Hsp90 is an essential component of cytoplasmic Hsp90-Hsp70 chaperone network, responsible for protein folding. Protein emerging from ribosome is initially folded in nascent polypeptide by Hsp70 and then passed to the Hsp90 for later folding. GRP94, the hsp90 family chaperone, hydrolysis the ATP, facilitates protein folding and liable for the maturation of certain oligomeric proteins including Toll-like receptors (Table 1) [58].

Chaperone familyER chaperoneFunction
Heat shock proteins
GRP78/BiPFacilitates folding and assembly of proteins, translocates the newly synthesized polypeptides, targets misfolded proteins for ERAD, regulates calcium homeostasis [27].
GRP94/endoplasminDirects the oxidative folding and assembly of several secreted and membrane proteins that mainly contain disulphide bonds.
Lectin chaperones
CalnexinTransmembrane protein binds to glycan residues of nascent polypeptides found in membrane proximal domains and retains substrate proteins in the ER until they are fully mature and their intermediate oligosaccharide is cleaved by glucosidase II [55].
CalreticulinSoluble luminal homolog associates with glycans within the ER lumen and interacts with monoglucosylated glycans, trimmed intermediates of N-linked core glycans on nascent glycoproteins [56].
Thiol oxireductases
ERp57/PDIA3Participates in the folding of numerous cysteine-rich glycoproteins as an element of the CNX/CRT cycle [55].
PDI/PDIA1/P4HBAssists in redox protein folding via oxidation, multiple thiol-disulphide exchanges, isomerization, reduction activities and is highly specific in its interaction with different substrates [57].
ERdj5Catalyzes the removal of non-native disulfides by binding with BiP and ensures the correct folding of proteins entering the secretory pathway or dislocates misfolded proteins to the cytosol for degradation [54].

Table 1.

Classification of ER chaperones and their functional roles.

6.2 Lectin chaperones

A unique aspect of the ER involves glycosylation-assisted folding which is largely mediated by ER resident lectins. There are two calcium-activating chaperones in the ER - calnexin (CNX) and calreticulin (CRT), that associates with glycoproteins and completes the protein folding process [55, 59]. The CNX/CRT cycle is critical part of the ER quality control machinery in monitoring the glycosylation and sugar chain structures in protein folding and assembly. When one glucose residue is attached to the client protein, ER lectins bind to initiate the folding process and later release the protein to UDP-glucose-glycoprotein glucosyltransferase. The disulfide bond isomerase ER protein 57 (ERp57) majorly involved in the CNX/CRT cycle, catalyzes the oxidation and isomerization of the disulfide bonds in glycoproteins. Further, CRT elicits an immune response through the assembly of major histocompatibility complex (MHC) class I molecules for eventual antigen presentation on the cell surface, intended for apoptosis [60].

6.3 Thiol oxireductases

Formation of transient disulfide bonds in the protein folding process are mediated by thiol oxidoreductases and are essential for the activation of the PERK pathway [56]. These are the major proteins that redox control by utilizing catalytic cysteine residues for oxidation or reduction of their substrates. Protein disulphide isomerase (PDI), ERp72, ERp61, GRP58/ERp57, ERp44 and ERp29 are enzymes that mediate the formation of disulphide bonds through oxidizing cysteine residues of nascent proteins. However, most of the thioloxidoreductases act as oxidants [61] and in certain cancer models, ERp57 as well as PERK gets activated in a PDI dependent manner, reducing cancer cell proliferation and sensitizes cancer cells to ionizing radiation [62].

Hsp47 (Serpin H1) is an ER-resident collagen-specific molecular chaperone that is essential for molecular maturation of collagen. Hsp47 binds Yaa-Gly-Xaa-Arg-Gly in triple-helical procollagen in the ER via hydrophobic and hydrophilic interactions. The binding of Hsp47 stabilizes procollagen by preventing unfolding of the triple helix and aggregate formation. Thus, Hsp47 is indispensable for efficient secretion, processing, fibril formation, and deposition of collagen in the extracellular matrix [63]. The chaperone function of Hsp47 is also involved in the deterioration of fibrosis, suggesting Hsp47 as a therapeutic target for fibrotic diseases, including liver, lung and spleen fibrosis. Lipase maturation factor 1 (LMF1) is an ER chaperone that affects ER lipid metabolism through the activation of lipoprotein, hepatic and endothelial lipases [64]. Mutations in LMF1 are associated with severe hypertriglyceridemia caused by deficiency of these lipases.

Advertisement

7. Conclusion

Preeclampsia is the most frequently encountered medical complication in pregnancy that affects 3–7% of pregnant women worldwide, characterized by de novo on-set of hypertension, proteinuria after 20 weeks of gestation, entailing the heterogeneous etiological disease manifestations. Placental dysfunction due to reduced perfusion, trophoblast remodeling, oxidative stress, ER stress and exaggerated inflammatory response are the major factors that contributes to early on-set preeclampsia. Numerous reports substantiate that ER stress, protein misfolding and aggregation are the major inducers behind the etiological manifestations of PE, leading to disease pathogenesis [65, 66]. Furthermore, amyloid fibrous protein aggregates are an emerging biomarker of PE representing amyloid aggregation of amyloid β, transthyretin, immunoglobulin light chains and alpha-1 antitrypsin. These aggregated proteins mediate defective trophoblast invasion and abnormal remodeling of spiral arteries leading to the onset of PE. This unveils new strategies to identify novel biomarkers as well as targets for therapeutic intervention, to alleviate the underlying pathological conditions and decrease the risk of preeclampsia.

Advertisement

Conflict of interest

The authors declare no conflict of interest.

References

  1. 1.Rana S, Lemoine E, Granger JP, Karumanchi SA. Preeclampsia: Pathophysiology, challenges, and perspectives. Circulation Research. 2019;124(7):1094-1112. DOI: 10.1161/CIRCRESAHA.118.313276
  2. 2.Shamshirsaz AA, Paidas M, Krikun G. Preeclampsia, hypoxia, thrombosis, and inflammation. Journal of Pregnancy. 2012;2012:1-6
  3. 3.Burton GJ, Yung HW, Murray AJ. Mitochondrial-endoplasmic reticulum interactions in the trophoblast: Stress and senescence. Placenta. 2017;52:146-155
  4. 4.Engin F, Hotamisligil GS. Restoring endoplasmic reticulum function by chemical chaperones: An emerging therapeutic approach for metabolic diseases. Diabetes, Obesity & Metabolism. 2010;2:108-115
  5. 5.Ozcan L, Tabas I. Role of endoplasmic reticulum stress in metabolic disease and other disorders. Annual Review of Medicine. 2012;63:317-328
  6. 6.Oakes SA, Papa FR. The role of endoplasmic reticulum stress in human pathology. Annual Review of Pathology. 2015;10:173-194
  7. 7.Garcia-Huerta P, Bargsted L, Rivas A, Matus S, Vidal RL. ER chaperones in neurodegenerative disease: Folding and beyond. Brain Research. 2016;1648(Pt B):580-587
  8. 8.Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet. 2010;376(9741):631-644
  9. 9.Redman CW. Preeclampsia: A multi-stress disorder. La Revue de Médecine Interne. 2011;32(Suppl. 1):S41-S44
  10. 10.Gerasimova EM, Fedotov SA, Kachkin DV, Vashukova ES, Glotov AS, Chernoff YO, et al. Protein misfolding during pregnancy: New approaches to preeclampsia diagnostics. International Journal of Molecular Sciences. 2019;20(24):6183. DOI: 10.3390/ijms20246183
  11. 11.Anelli T, Sitia R. Protein quality control in the early secretory pathway. The EMBO Journal. 2008;27:315-327
  12. 12.Pizzo P, Pozzan T. Mitochondria-endoplasmic reticulum choreography: Structure and signaling dynamics. Trends in Cell Biology. 2007;17:511-517
  13. 13.Ma Y, Hendershot LM. ER chaperone functions during normal and stress conditions. Journal of Chemical Neuroanatomy. 2004;28(1-2):51-65. DOI: 10.1016/j.jchemneu.2003.08.007
  14. 14.Rizzuto R, Duchen MR, Pozzan T. Flirting in little space: The ER/mitochondria Ca2+ liaison. Science’s STKE. 2004;2004:re1
  15. 15.Schroder M, Kaufman RJ. ER stress and the unfolded protein response. Mutation Research. 2005;569:29-63
  16. 16.Xu C, Bailly-Maitre B, Reed JC. Endoplamic reticulum stress: Cell life and death decisions. The Journal of Clinical Investigation. 2005;115:2656-2664
  17. 17.Wu J, Kaufman RJ. From acute ER stress to physiological roles of the unfolded protein response. Cell Death and Differentiation. 2006;13:374-384
  18. 18.Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nature Reviews Molecular Cell Biology. 2007;8:519-529
  19. 19.Malhotra JD, Kaufman RJ. The endoplasmic reticulum and the unfolded protein response. Seminars in Cell & Developmental Biology. 2007;18:716-731
  20. 20.Cox JS, Shamu CE, Walter P. Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase. Cell. 1993;73(6):1197-1206. DOI: 10.1016/0092-8674(93)90648-a
  21. 21.Harding HP, Zhang Y, Ron D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature. 1999;397(6716):271-274. DOI: 10.1038/16729
  22. 22.Haze K, Yoshida H, Yanagi H, Yura T, Mori K. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Molecular Biology of the Cell. 1999;10(11):3787-3799. DOI: 10.1091/mbc.10.11.3787
  23. 23.Walter P, Ron D. The unfolded protein response: From stress pathway to homeostatic regulation. Science. 2011;334(6059):1081-1086. DOI: 10.1126/science.1209038
  24. 24.Shen J, Chen X, Hendershot L, Prywes R. ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Developmental Cell. 2002;3(1):99-111. DOI: 10.1016/s1534-5807(02)00203-4
  25. 25.Lee AH, Iwakoshi NN, Glimcher LH. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Molecular and Cellular Biology. 2003;23:7448-7459
  26. 26.Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K. XBP1 mrna is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell. 2001;107:881-891
  27. 27.Lee AS. The ER chaperone and signaling regulator GRP78/BiP as a monitor of endoplasmic reticulum stress. Methods. 2005;35:373-381
  28. 28.Kim I, Xu W, Reed JC. Cell death and endoplasmic reticulum stress: Disease relevance and therapeutic opportunities. Nature Reviews. Drug Discovery. 2008;7:1013-1030
  29. 29.Rutkowski DT, Kaufman RJ. That which does not kill me makes me stronger: Adapting to chronic ER stress. Trends in Biochemical Sciences. 2007;32:469-476
  30. 30.Kadowaki H, Nishitoh H. Signaling pathways from the endoplasmic reticulum and their roles in disease. Genes. 2013;4:306-333
  31. 31.Michalak M, Gye MC. Endoplasmic reticulum stress in periimplantation embryos. Clinical and Experimental Reproductive Medicine. 2015;42:1-7
  32. 32.Bifulco G, Miele C, di Jeso B, Beguinot F, Nappi C, di Carlo C, et al. Endoplasmic reticulum stress is activated in endometrial adenocarcinoma. Gynecologic Oncology. 2012;125:220-225
  33. 33.Yung HW, Atkinson D, Campion-Smith T, Olovsson M, Charnock-Jones DS, Burton GJ. Differential activation of placental unfolded protein response pathways implies heterogeneity in causation of early- and late-onset pre-eclampsia. The Journal of Pathology. 2014;234:262-276
  34. 34.Buhimschi IA, Nayeri UA, Zhao G, Shook LL, Pensalfini A, Funai EF, et al. Protein misfolding, congophilia, oligomerization, and defective amyloid processing in preeclampsia. Science Translational Medicine. 2014;6:245ra92
  35. 35.Kalkunte SS, Neubeck S, Norris WE, Cheng S-B, Kostadinov S, Vu Hoang D, et al. Transthyretin is dysregulated in preeclampsia, and its native form prevents the onset of disease in a preclinical mouse model. The American Journal of Pathology. 2013;183:1425-1436
  36. 36.Yoshida H. ER stress and diseases. The FEBS Journal. 2007;274(3):630-658. DOI: 10.1111/j.1742-4658.2007.05639.x
  37. 37.Mekahli D, Bultynck G, Parys JB, De Smedt H, Missiaen L. Endoplasmic-reticulum calcium depletion and disease. Cold Spring Harbor Perspectives in Biology. 2011;3(6):a004317. DOI: 10.1101/cshperspect.a004317
  38. 38.Chaiworapongsa T, Chaemsaithong P, Yeo L, Romero R. Preeclampsia part 1: Current understanding of its pathophysiology. Nature Reviews. Nephrology. 2014;10:466-480
  39. 39.Goel A, Rana S. Angiogenic factors in preeclampsia: Potential for diagnosis and treatment. Current Opinion in Nephrology and Hypertension. 2013;22:643-650
  40. 40.Redman CW, Sargent IL. Latest advances in understanding preeclampsia. Science. 2005;308:1592-1594
  41. 41.Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Preeclampsia. Lancet. 2010;376:631-644
  42. 42.Cheng SB, Nakashima A, Sharma S. Understanding pre-eclampsia using Alzheimer’s etiology: An intriguing viewpoint. American Journal of Reproductive Immunology. 2016;75(3):372-381. DOI: 10.1111/aji.12446. Epub 2015 Nov 20
  43. 43.Burton GJ, Yung HW. Endoplasmic reticulum stress in the pathogenesis of early-onset pre-eclampsia. Pregnancy Hypertension. 2011;1(1-2):72-78. DOI: 10.1016/j.preghy.2010.12.002
  44. 44.Yung HW, Calabrese S, Hynx D, Hemmings BA, Cetin I, Charnock-Jones DS. Evidence of placental translation inhibition and endoplasmic reticulum stress in the etiology of human intrauterine growth restriction. The American Journal of Pathology. 2008;173:451-462
  45. 45.Du L, He F, Kuang L, Tang W, Li Y, Chen D. eNOS/iNOS and endoplasmic reticulum stress-induced apoptosis in the placentas of patients with preeclampsia. Journal of Human Hypertension. 2017;31:49-55
  46. 46.Cindrova-Davies T. The therapeutic potential of antioxidants, ER chaperones, NO and H2S donors, and statins for treatment of preeclampsia. Frontiers in Pharmacology. 2014;5:119. DOI: 10.3389/fphar.2014.00119
  47. 47.Halperin L, Jung J, Michalak M. The many functions of the endoplasmic reticulum chaperones and folding enzymes. IUBMB Life. 2014;66:318-326. DOI: 10.1002/iub.1272
  48. 48.Guzel E, Arlier S, Guzeloglu-Kayisli O, Tabak MS, Ekiz T, Semerci N, et al. Endoplasmic reticulum stress and homeostasis in reproductive physiology and pathology. International Journal of Molecular Sciences. 2017;18(4):792. DOI: 10.3390/ijms18040792
  49. 49.Ikwegbue, Chukwudi P, Revaprasadu N, Kappo AP. Therapeutic potential of heat shock proteins in human inflammation/autoimmune skin diseases: Future directions. In: Asea AAA, Kaur P, editors. Heat Shock Proteins in Inflammatory Diseases. Vol. 22. Cham: Springer; 2020. pp. 1-16. DOI: 10.1007/7515_2020_36
  50. 50.Burdon RH. Heat shock and the heat shock proteins. Biochemical Journal. 1986;240(2):313
  51. 51.Meriin AB, Sherman MY. Role of molecular chaperones in neurodegenerative disorders. International Journal of Hyperthermia. 2005;21(5):403-419
  52. 52.Saghafi N, Pourali L, Ghanbarabadi VG, Mirzamarjani F, Mirteimouri M. Serum heat shock protein 70 in preeclampsia and normal pregnancy: A systematic review and meta analysis. International Journal of Reproductive BioMedicine. 2018;16(1):1
  53. 53.Garrido C, Gurbuxani S, Ravagnan L, Kroemer G. Heat shock proteins: Endogenous modulators of apoptotic cell death. Biochemical and Biophysical Research Communications. 2001;286:433-442
  54. 54.Parcellier A, Gurbuxani S, Schmitt E, Solary E, Garrido C. Heat shock proteins, cellular chaperones that modulate mitochondrial cell death pathways. Biochemical and Biophysical Research Communications. 2003;304:505-512
  55. 55.Wu Y, Huang X, Zheng Z, Yang X, Ba Y, Lian J. Role and mechanism of chaperones calreticulin and ERP57 in restoring trafficking to mutant HERG A561V protein. International Journal of Molecular Medicine. 2021;48(2):1-12
  56. 56.Venkatesan A, Satin LS, Raghavan M. Roles of calreticulin in protein folding, immunity, calcium signaling and cell transformation. In: Cellular Biology of the Endoplasmic Reticulum. Cham: Springer; 2021. pp. 145-162
  57. 57.Parakh S, Atkin JD. Novel roles for protein disulphide isomerase in disease states: A double edged sword? Frontiers in Cell and Developmental Biology. 2015;3:30. DOI: 10.3389/fcell.2015.00030
  58. 58.Lackie RE, Maciejewski A, Ostapchenko VG, Marques-Lopes J, Choy WY, Duennwald ML, et al. The Hsp70/Hsp90 chaperone machinery in neurodegenerative diseases. Frontiers in Neuroscience. 2017;11:254. DOI: 10.3389/fnins.2017.00254
  59. 59.Moezzi SMI, Mozafari N, Fazel-Hoseini SM, Nadimi-Parashkoohi S, Abbasi H, Ashrafi H, et al. Apolipoprotein J in Alzheimer’s disease: Shedding light on its role with cell signaling pathway perspective and possible therapeutic approaches. ACS Chemical Neuroscience. 2020;11(24):4060-4072
  60. 60.Graner MW, Lillehei KO, Katsanis E. Endoplasmic reticulum chaperones and their roles in the immunogenicity of cancer vaccines. Frontiers in Oncology. 2015;4:379. DOI: 10.3389/fonc.2014.00379
  61. 61.Bocian-Ostrzycka KM, Grzeszczuk MJ, Banaś AM, Jagusztyn-Krynicka EK. Bacterial thioloxidoreductases—From basic research to new antibacterial strategies. Applied Microbiology and Biotechnology. 2017;101(10):3977-3989
  62. 62.Kranz P, Sänger C, Wolf A, Baumann J, Metzen E, Baumann M, et al. Tumor cells rely on the thiol-oxidoreductase PDI for PERK signaling in order to survive ER stress. Scientific Reports. 2020;10(1):1-11
  63. 63.Ito S, Nagata K. Biology of Hsp47 (Serpin H1), a collagen-specific molecular chaperone. Seminars in Cell & Developmental Biology. 2016;62:142-151. DOI: 10.1016/j.semcdb.2016.11.005
  64. 64.Péterfy M. Lipase maturation factor 1: A lipase chaperone involved in lipid metabolism. Biochimica et Biophysica Acta. 2012;1821(5):790-794. DOI: 10.1016/j.bbalip.2011.10.006
  65. 65.Wang M, Kaufman RJ. Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature. 2016;529:326-335. DOI: 10.1038/nature17041
  66. 66.Hetz C, Papa FR. The unfolded protein response and cell fate control. Molecular Cell. 2017;69:169-181. DOI: 10.1016/j.molcel.2017.06.017

Written By

Janaranjani Murugesan, Ajithkumar Balakrishnan, Premkumar Kumpati and Hemamalini Vedagiri

Submitted: October 11th, 2021Reviewed: October 18th, 2021Published: December 26th, 2021