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Physiological and Pathological Aspects of Unfolded Protein Response 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 27238

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Dr. Michele Sallese

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Department of Medical, Oral and Biotechnological Sciences, ‘G. d’Annunzio’ University of Chieti–Pescara, 66100 Chieti, Italy
Interests: misfolding diseases; unfolded protein response; membrane trafficking; gluten related disorders; gene expression; cell signaling; cell invasion
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Dear Colleagues,

Protein homeostasis, or proteostasis, is a dynamic process involving the continuous degradation and replacement of damaged proteins with newly synthesized proteins. Proteins are synthesised by ribosomes as unstructured polypeptides when, thanks to dedicated folding machinery involving high energy expenditure, the polypeptides acquire the correct three-dimensional structure. Indeed, some proteins are inherently difficult to fold and the fraction of them that remain misshapen has to be discarded. Meanwhile, some polypeptides that carry point mutations cannot be folded at all. Mutations can also affect and damage the folding machinery itself.

Accumulation of unfolded proteins activates the unfolded protein response (UPR), a signalling and transcriptional programme aimed at coping with cellular stress due to misfolding. UPR involves three ER stress sensors, namely PERK, IRE1, and ATF6, which trigger various molecular responses with the aim of reducing protein synthesis and enhancing folding and/or degradation of misfolded proteins. If these measures do not allow the stress to be overcome, the UPR activates apoptotic cell death.

Notably, a number of human diseases involve an alteration of proteostasis. The loss of important functions and/or toxic gains of function are the main mechanisms of these misfolding diseases. In the first group of diseases, misshapen proteins never reach their final destination because the ER quality control systems recognize and direct them to disposal (for example, via proteasome or autophagolysosome). In the second group, unfolded proteins aggregate and lead to cellular toxicity through different mechanisms. To date, the therapeutic options for misfolding diseases are rather limited. Pioneering studies have shown that neurodegenerative diseases can have some benefits from inhibiting or activating the UPR, depending on the specific disease. However, it is absolutely necessary to study more effective strategies to improve the quality of life of these patients.

This overview is not exhaustive but covers possible topics welcome in this Special Issue. I am confident that a number of additional aspects on human diseases involving misfolded proteins will be proposed.

Both original articles, reviews and commentaries are welcome.

Dr. Michele Sallese
Guest Editor

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Keywords

human diseases
protein folding machinery
unfolded protein response
ER associated degradation
ER-to-lysosome-associated degradation
toxic gain-of-function
pathogenic pathways
innovative therapeutic strategies

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Physiological and Pathological Aspects of Unfolded Protein Response in International Journal of Molecular Sciences (5 articles)

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Research

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16 pages, 6904 KiB

Open AccessArticle

The Unfolded Protein Response Sensor IRE1 Regulates Activation of In Vitro Differentiated Type 1 Conventional DCs with Viral Stimuli

by Bernardita Medel, José Ignacio Bernales, Alonso Lira, Dominique Fernández, Takao Iwawaki, Pablo Vargas and Fabiola Osorio

Int. J. Mol. Sci. 2023, 24(12), 10205; https://doi.org/10.3390/ijms241210205 - 16 Jun 2023

Viewed by 1533

Abstract

Type 1 conventional dendritic cells (cDC1s) are leukocytes competent to coordinate antiviral immunity, and thus, the intracellular mechanisms controlling cDC1 function are a matter of intense research. The unfolded protein response (UPR) sensor IRE1 and its associated transcription factor XBP1s control relevant functional aspects in cDC1s including antigen cross-presentation and survival. However, most studies connecting IRE1 and cDC1 function are undertaken in vivo. Thus, the aim of this work is to elucidate whether IRE1 RNase activity can also be modeled in cDC1s differentiated in vitro and reveal the functional consequences of such activation in cells stimulated with viral components. Our data show that cultures of optimally differentiated cDC1s recapitulate several features of IRE1 activation noticed in in vivo counterparts and identify the viral analog Poly(I:C) as a potent UPR inducer in the lineage. In vitro differentiated cDC1s display constitutive IRE1 RNase activity and hyperactivate IRE1 RNase upon genetic deletion of XBP1s, which regulates production of the proinflammatory cytokines IL-12p40, TNF-α and IL-6, Ifna and Ifnb upon Poly(I:C) stimulation. Our results show that a strict regulation of the IRE1/XBP1s axis regulates cDC1 activation to viral agonists, expanding the scope of this UPR branch in potential DC-based therapies. Full article

(This article belongs to the Special Issue Physiological and Pathological Aspects of Unfolded Protein Response 2.0)

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13 pages, 1639 KiB

Open AccessArticle

GADD34 Ablation Exacerbates Retinal Degeneration in P23H RHO Mice

by Irina V. Saltykova, Assylbek Zhylkibayev, Oleg S. Gorbatyuk and Marina S. Gorbatyuk

Int. J. Mol. Sci. 2022, 23(22), 13748; https://doi.org/10.3390/ijms232213748 - 9 Nov 2022

Cited by 2 | Viewed by 1491

Abstract

The UPR is sustainably activated in degenerating retinas, leading to translational inhibition via p-eIF2α. Recent findings have demonstrated that ablation of growth arrest and DNA damage-inducible protein 34 (GADD34), a protein phosphatase 1 regulatory subunit permitting translational machinery operation through p-eIF2α elevation, does not impact the rate of translation in fast-degenerating rd16 mice. The current study aimed to validate whether P23H RHO mice degenerating at a slower pace manifest translational attenuation and whether GADD34 ablation impacts the rate of retinal degeneration via further suppression of retinal protein synthesis and apoptotic cell death. For this study, mice were examined with ERG and histological analyses. The molecular assessment was conducted in the naïve and LPS-challenged mice using Western blot and qRT-PCR analyses. Thus, this study demonstrates that the P23H RHO retinas manifest translational attenuation. However, GADD34 ablation resulted in a more prominent p-eIF2a increase without impacting the translation rate. GADD34 deficiency also led to a reduction in scotopic ERG amplitudes and an increased number of TUNEL-positive cells. Molecular analysis revealed that GADD34 deficiency reduces the expression of p-STAT3 and Il-6 while increasing the expression of Tnfa. Overall, the data indicate that GADD34 plays a multifunctional role. Under chronic UPR activation, GADD34 acts as a feedback player, dephosphorylating p-eIF2a, although this role does not seem to be critical. Additionally, GADD34 controls cytokine expression and STAT3 activation. Perhaps these molecular events are particularly important in controlling the pace of retinal degeneration. Full article

(This article belongs to the Special Issue Physiological and Pathological Aspects of Unfolded Protein Response 2.0)

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14 pages, 7341 KiB

Open AccessArticle

Diverse Sphingolipid Species Harbor Different Effects on Ire1 Clustering

by Mark A. Bieniawski, Kofi L. P. Stevens, Christopher M. Witham, Robert F. L. Steuart, Vytas A. Bankaitis and Carl J. Mousley

Int. J. Mol. Sci. 2022, 23(20), 12130; https://doi.org/10.3390/ijms232012130 - 12 Oct 2022

Cited by 2 | Viewed by 1393

Abstract

Endoplasmic reticulum (ER) function is dedicated to multiple essential processes in eukaryotes, including the processing of secretory proteins and the biogenesis of most membrane lipids. These roles implicate a heavy burden to the organelle, and it is thus prone to fluctuations in the homeostasis of molecules which govern these processes. The unfolded protein response (UPR) is a general ER stress response tasked with maintaining the ER for optimal function, mediated by the master activator Ire1. Ire1 is an ER transmembrane protein that initiates the UPR, forming characteristic oligomers in response to irregularities in luminal protein folding and in the membrane lipid environment. The role of lipids in regulating the UPR remains relatively obscure; however, recent research has revealed a potent role for sphingolipids in its activity. Here, we identify a major role for the oxysterol-binding protein Kes1, whose activity is of consequence to the sphingolipid profile in cells resulting in an inhibition of UPR activity. Using an mCherry-tagged derivative of Ire1, we observe that this occurs due to inhibition of Ire1 to form oligomers. Furthermore, we identify that a sphingolipid presence is required for Ire1 activity, and that specific sphingolipid profiles are of major consequence to Ire1 function. In addition, we highlight cases where Ire1 oligomerization is absent despite an active UPR, revealing a potential mechanism for UPR induction where Ire1 oligomerization is not necessary. This work provides a basis for the role of sphingolipids in controlling the UPR, where their metabolism harbors a crucial role in regulating its onset. Full article

(This article belongs to the Special Issue Physiological and Pathological Aspects of Unfolded Protein Response 2.0)

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13 pages, 2734 KiB

Open AccessArticle

Small Heat Shock Proteins Collaborate with FAIM to Prevent Accumulation of Misfolded Protein Aggregates

by Hiroaki Kaku, Allison R. Balaj and Thomas L. Rothstein

Int. J. Mol. Sci. 2022, 23(19), 11841; https://doi.org/10.3390/ijms231911841 - 6 Oct 2022

Cited by 4 | Viewed by 2221

Abstract

Cells and tissues are continuously subject to environmental insults, such as heat shock and oxidative stress, which cause the accumulation of cytotoxic, aggregated proteins. We previously found that Fas Apoptosis Inhibitory Molecule (FAIM) protects cells from stress-induced cell death by preventing abnormal generation of protein aggregates similar to the effect of small heat shock proteins (HSPs). Protein aggregates are often associated with neurodegenerative diseases, including Alzheimer’s disease (AD). In this study, we sought to determine how FAIM protein dynamics change during cellular stress and how FAIM prevents the formation of amyloid-β aggregates/fibrils, one of the pathological hallmarks of AD. Here, we found that the majority of FAIM protein shifts to the detergent-insoluble fraction in response to cellular stress. A similar shift to the insoluble fraction was also observed in small heat shock protein (sHSP) family molecules, such as HSP27, after stress. We further demonstrate that FAIM is recruited to sHSP-containing complexes after cellular stress induction. These data suggest that FAIM might prevent protein aggregation in concert with sHSPs. In fact, we observed the additional effect of FAIM and HSP27 on the prevention of protein aggregates using an in vitro amyloid-β aggregation model system. Our work provides new insights into the interrelationships among FAIM, sHSPs, and amyloid-β aggregation. Full article

(This article belongs to the Special Issue Physiological and Pathological Aspects of Unfolded Protein Response 2.0)

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20 pages, 4744 KiB

Open AccessArticle

Caffeine and MDMA (Ecstasy) Exacerbate ER Stress Triggered by Hyperthermia

by Kathleen A. Trychta and Brandon K. Harvey

Int. J. Mol. Sci. 2022, 23(4), 1974; https://doi.org/10.3390/ijms23041974 - 10 Feb 2022

Cited by 2 | Viewed by 6578

Abstract

Drugs of abuse can cause local and systemic hyperthermia, a known trigger of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Another trigger of ER stress and UPR is ER calcium depletion, which causes ER exodosis, the secretion of ER-resident proteins. In rodent models, club drugs such as 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) can create hyperthermic conditions in the brain and cause toxicity that is affected by the environmental temperature and the presence of other drugs, such as caffeine. In human studies, MDMA stimulated an acute, dose-dependent increase in core body temperature, but an examination of caffeine and MDMA in combination remains a topic for clinical research. Here we examine the secretion of ER-resident proteins and activation of the UPR under combined exposure to MDMA and caffeine in a cellular model of hyperthermia. We show that hyperthermia triggers the secretion of normally ER-resident proteins, and that this aberrant protein secretion is potentiated by the presence of MDMA, caffeine, or a combination of the two drugs. Hyperthermia activates the UPR but the addition of MDMA or caffeine does not alter the canonical UPR gene expression despite the drug effects on ER exodosis of UPR-related proteins. One exception was increased BiP/GRP78 mRNA levels in MDMA-treated cells exposed to hyperthermia. These findings suggest that club drug use under hyperthermic conditions exacerbates disruption of ER proteostasis, contributing to cellular toxicity. Full article

(This article belongs to the Special Issue Physiological and Pathological Aspects of Unfolded Protein Response 2.0)

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11 pages, 3027 KiB

Open AccessArticle

Induction of the Unfolded Protein Response at High Temperature in Saccharomyces cerevisiae

by Tatsuya Hata, Yuki Ishiwata-Kimata and Yukio Kimata

Int. J. Mol. Sci. 2022, 23(3), 1669; https://doi.org/10.3390/ijms23031669 - 31 Jan 2022

Cited by 4 | Viewed by 2499

Abstract

Ire1 is an endoplasmic reticulum (ER)-located endoribonuclease that is activated in response to ER stress. In yeast Saccharomyces cerevisiae cells, Ire1 promotes HAC1-mRNA splicing to remove the intron sequence from the HAC1u mRNA (“u” stands for “uninduced”). The resulting mRNA, which is named HAC1i mRNA (“i” stands for “induced”), is then translated into a transcription factor that is involved in the unfolded protein response (UPR). In this study, we designed an oligonucleotide primer that specifically hybridizes to the exon-joint site of the HAC1i cDNA. This primer allowed us to perform real-time reverse transcription-PCR to quantify HAC1i mRNA abundance with high sensitivity. Using this method, we detected a minor induction of HAC1-mRNA splicing in yeast cells cultured at their maximum growth temperature of 39 °C. Based on our analyses of IRE1-gene mutant strains, we propose that when yeast cells are cultured at or near their maximum growth temperature, protein folding in the ER is disturbed, leading to a minor UPR induction that supports cellular growth. Full article

(This article belongs to the Special Issue Physiological and Pathological Aspects of Unfolded Protein Response 2.0)

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17 pages, 1946 KiB

Open AccessArticle

ER Unfolded Protein Response in Liver In Vivo Is Characterized by Reduced, Not Increased, De Novo Lipogenesis and Cholesterol Synthesis Rates with Uptake of Fatty Acids from Adipose Tissue: Integrated Gene Expression, Translation Rates and Metabolic Fluxes

by Catherine P. Ward, Lucy Peng, Samuel Yuen, Michael Chang, Rozalina Karapetyan, Edna Nyangau, Hussein Mohammed, Hector Palacios, Naveed Ziari, Larry K. Joe, Ashley E. Frakes, Mohamad Dandan, Andrew Dillin and Marc K. Hellerstein

Int. J. Mol. Sci. 2022, 23(3), 1073; https://doi.org/10.3390/ijms23031073 - 19 Jan 2022

Cited by 8 | Viewed by 3265

Abstract

The unfolded protein response in the endoplasmic reticulum (UPR^ER) is involved in a number of metabolic diseases. Here, we characterize UPR^ER-induced metabolic changes in mouse livers in vivo through metabolic labeling and mass spectrometric analysis of lipid and proteome-wide fluxes. We induced UPR^ER by tunicamycin administration and measured synthesis rates of proteins, fatty acids and cholesterol, as well as RNA-seq. Contrary to reports in isolated cells, hepatic de novo lipogenesis and cholesterogenesis were markedly reduced, as were mRNA levels and synthesis rates of lipogenic proteins. H&E staining showed enrichment with lipid droplets while electron microscopy revealed ER morphological changes. Interestingly, the pre-labeling of adipose tissue prior to UPR^ER induction resulted in the redistribution of labeled fatty acids from adipose tissue to the liver, with replacement by unlabeled glycerol in the liver acylglycerides, indicating that the liver uptake was of free fatty acids, not whole glycerolipids. The redistribution of adipose fatty acids to the liver was not explicable by altered plasma insulin, increased fatty acid levels (lipolysis) or by reduced food intake. Synthesis of most liver proteins was suppressed under UPR^ER conditions, with the exception of BiP, other chaperones, protein disulfide isomerases, and proteins of ribosomal biogenesis. Protein synthesis rates generally, but not always, paralleled changes in mRNA. In summary, this combined approach, linking static changes with fluxes, revealed an integrated reduction of lipid and cholesterol synthesis pathways, from gene expression to translation and metabolic flux rates, under UPR^ER conditions. The reduced lipogenesis does not parallel human fatty liver disease. This approach provides powerful tools to characterize metabolic processes underlying hepatic UPR^ER in vivo. Full article

(This article belongs to the Special Issue Physiological and Pathological Aspects of Unfolded Protein Response 2.0)

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19 pages, 29658 KiB

Open AccessArticle

Proteomic Analysis of Marinesco–Sjogren Syndrome Fibroblasts Indicates Pro-Survival Metabolic Adaptation to SIL1 Loss

by Francesca Potenza, Maria Concetta Cufaro, Linda Di Biase, Valeria Panella, Antonella Di Campli, Anna Giulia Ruggieri, Beatrice Dufrusine, Elena Restelli, Laura Pietrangelo, Feliciano Protasi, Damiana Pieragostino, Vincenzo De Laurenzi, Luca Federici, Roberto Chiesa and Michele Sallese

Int. J. Mol. Sci. 2021, 22(22), 12449; https://doi.org/10.3390/ijms222212449 - 18 Nov 2021

Cited by 9 | Viewed by 3385

Abstract

Marinesco–Sjogren syndrome (MSS) is a rare multisystem pediatric disorder, caused by loss-of-function mutations in the gene encoding the endoplasmic reticulum cochaperone SIL1. SIL1 acts as a nucleotide exchange factor for BiP, which plays a central role in secretory protein folding. SIL1 mutant cells have reduced BiP-assisted protein folding, cannot fulfil their protein needs, and experience chronic activation of the unfolded protein response (UPR). Maladaptive UPR may explain the cerebellar and skeletal muscle degeneration responsible for the ataxia and muscle weakness typical of MSS. However, the cause of other more variable, clinical manifestations, such as mild to severe mental retardation, hypogonadism, short stature, and skeletal deformities, is less clear. To gain insights into the pathogenic mechanisms and/or adaptive responses to SIL1 loss, we carried out cell biological and proteomic investigations in skin fibroblasts derived from a young patient carrying the SIL1 R111X mutation. Despite fibroblasts not being overtly affected in MSS, we found morphological and biochemical changes indicative of UPR activation and altered cell metabolism. All the cell machineries involved in RNA splicing and translation were strongly downregulated, while protein degradation via lysosome-based structures was boosted, consistent with an attempt of the cell to reduce the workload of the endoplasmic reticulum and dispose of misfolded proteins. Cell metabolism was extensively affected as we observed a reduction in lipid synthesis, an increase in beta oxidation, and an enhancement of the tricarboxylic acid cycle, with upregulation of eight of its enzymes. Finally, the catabolic pathways of various amino acids, including valine, leucine, isoleucine, tryptophan, lysine, aspartate, and phenylalanine, were enhanced, while the biosynthetic pathways of arginine, serine, glycine, and cysteine were reduced. These results indicate that, in addition to UPR activation and increased protein degradation, MSS fibroblasts have profound metabolic alterations, which may help them cope with the absence of SIL1. Full article

(This article belongs to the Special Issue Physiological and Pathological Aspects of Unfolded Protein Response 2.0)

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19 pages, 2129 KiB

Open AccessReview

Regulation of Translation, Translocation, and Degradation of Proteins at the Membrane of the Endoplasmic Reticulum

by Lea Daverkausen-Fischer, Margarethe Draga and Felicitas Pröls

Int. J. Mol. Sci. 2022, 23(10), 5576; https://doi.org/10.3390/ijms23105576 - 17 May 2022

Cited by 9 | Viewed by 3825

Abstract

The endoplasmic reticulum (ER) of mammalian cells is the central organelle for the maturation and folding of transmembrane proteins and for proteins destined to be secreted into the extracellular space. The proper folding of target proteins is achieved and supervised by a complex endogenous chaperone machinery. BiP, a member of the Hsp70 protein family, is the central chaperone in the ER. The chaperoning activity of BiP is assisted by ER-resident DnaJ (ERdj) proteins due to their ability to stimulate the low, intrinsic ATPase activity of BiP. Besides their co-chaperoning activity, ERdj proteins also regulate and tightly control the translation, translocation, and degradation of proteins. Disturbances in the luminal homeostasis result in the accumulation of unfolded proteins, thereby eliciting a stress response, the so-called unfolded protein response (UPR). Accumulated proteins are either deleterious due to the functional loss of the respective protein and/or due to their deposition as intra- or extracellular protein aggregates. A variety of metabolic diseases are known to date, which are associated with the dysfunction of components of the chaperone machinery. In this review, we will delineate the impact of ERdj proteins in controlling protein synthesis and translocation under physiological and under stress conditions. A second aspect of this review is dedicated to the role of ERdj proteins in the ER-associated degradation pathway, by which unfolded or misfolded proteins are discharged from the ER. We will refer to some of the most prominent diseases known to be based on the dysfunction of ERdj proteins. Full article

(This article belongs to the Special Issue Physiological and Pathological Aspects of Unfolded Protein Response 2.0)

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