bims-unfpre 2019-04-14 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2019–04–14
eight papers selected by
Susan Logue, University of Manitoba

The Unfolded Protein Response: A Key Player in Zika Virus-Associated Congenital Microcephaly.
Nitrosative stress drives heart failure with preserved ejection fraction.
Stressed: The Unfolded Protein Response in T Cell Development, Activation, and Function.
XBP1S Regulates MUC5B in a Promoter Variant-Dependent Pathway in IPF Airway Epithelia.
GRP78: A cell's response to stress.
C/EBPβ mediates palmitate-induced musclin expression via the regulation of PERK/ATF4 pathways in myotubes.
Endoplasmic reticulum-associated SKN-1A/Nrf1 mediates a cytoplasmic unfolded protein response and promotes longevity.
Ablation of the Chaperone Protein ERdj5 Results in a Sjögren's Syndrome-Like Phenotype in Mice, Consistent With an Upregulated Unfolded Protein Response in Human Patients.

Front Cell Neurosci. 2019 ;13 94

The Unfolded Protein Response: A Key Player in Zika Virus-Associated Congenital Microcephaly.

Christian Alfano, Ivan Gladwyn-Ng, Thérèse Couderc, Marc Lecuit, Laurent Nguyen.

  Zika virus (ZIKV) is a mosquito-borne virus that belongs to the Flaviviridae family, together with dengue, yellow fever, and West Nile viruses. In the wake of its emergence in the French Polynesia and in the Americas, ZIKV has been shown to cause congenital microcephaly. It is the first arbovirus which has been proven to be teratogenic and sexually transmissible. Confronted with this major public health challenge, the scientific and medical communities teamed up to precisely characterize the clinical features of congenital ZIKV syndrome and its underlying pathophysiological mechanisms. This review focuses on the critical impact of the unfolded protein response (UPR) on ZIKV-associated congenital microcephaly. ZIKV infection of cortical neuron progenitors leads to high endoplasmic reticulum (ER) stress. This results in both the stalling of indirect neurogenesis, and UPR-dependent neuronal apoptotic death, and leads to cortical microcephaly. In line with these results, the administration of molecules inhibiting UPR prevents ZIKV-induced cortical microcephaly. The discovery of the link between ZIKV infection and UPR activation has a broader relevance, since this pathway plays a crucial role in many distinct cellular processes and its induction by ZIKV may account for several reported ZIKV-associated defects.

Keywords:  ER stress; Zika virus; cerebral cortex; cortical progenitors; microcephaly; unfolded protein response

DOI:  https://doi.org/10.3389/fncel.2019.00094
Nature. 2019 Apr 10.

Nitrosative stress drives heart failure with preserved ejection fraction.

Gabriele G Schiattarella, Francisco Altamirano, Dan Tong, Kristin M French, Elisa Villalobos, Soo Young Kim, Xiang Luo, Nan Jiang, Herman I May, Zhao V Wang, Theodore M Hill, Pradeep P A Mammen, Jian Huang, Dong I Lee, Virginia S Hahn, Kavita Sharma, David A Kass, Sergio Lavandero, Thomas G Gillette, Joseph A Hill.

Heart failure with preserved ejection fraction (HFpEF) is a common syndrome with high morbidity and mortality for which there are no evidence-based therapies. Here we report that concomitant metabolic and hypertensive stress in mice-elicited by a combination of high-fat diet and inhibition of constitutive nitric oxide synthase using Nω-nitro-L-arginine methyl ester (L-NAME)-recapitulates the numerous systemic and cardiovascular features of HFpEF in humans. Expression of one of the unfolded protein response effectors, the spliced form of X-box-binding protein 1 (XBP1s), was reduced in the myocardium of our rodent model and in humans with HFpEF. Mechanistically, the decrease in XBP1s resulted from increased activity of inducible nitric oxide synthase (iNOS) and S-nitrosylation of the endonuclease inositol-requiring protein 1α (IRE1α), culminating in defective XBP1 splicing. Pharmacological or genetic suppression of iNOS, or cardiomyocyte-restricted overexpression of XBP1s, each ameliorated the HFpEF phenotype. We report that iNOS-driven dysregulation of the IRE1α-XBP1 pathway is a crucial mechanism of cardiomyocyte dysfunction in HFpEF.

DOI: https://doi.org/10.1038/s41586-019-1100-z
Int J Mol Sci. 2019 Apr 11. pii: E1792. [Epub ahead of print]20(7):

Stressed: The Unfolded Protein Response in T Cell Development, Activation, and Function.

Kyeorda Kemp, Cody Poe.

  The unfolded protein response (UPR) is a highly conserved pathway that allows cells to respond to stress in the endoplasmic reticulum caused by an accumulation of misfolded and unfolded protein. This is of great importance to secretory cells because, in order for proteins to traffic from the endoplasmic reticulum (ER), they need to be folded appropriately. While a wealth of literature has implicated UPR in immune responses, less attention has been given to the role of UPR in T cell development and function. This review discusses the importance of UPR in T cell development, homeostasis, activation, and effector functions. We also speculate about how UPR may be manipulated in T cells to ameliorate pathologies.

Keywords:  ER stress; T cells; UPR; protein folding

DOI:  https://doi.org/10.3390/ijms20071792
Am J Respir Crit Care Med. 2019 Apr 11.

XBP1S Regulates MUC5B in a Promoter Variant-Dependent Pathway in IPF Airway Epithelia.

Gang Chen, Carla M P Ribeiro, Ling Sun, Kenichi Okuda, Takafumi Kato, Rodney C Gilmore, Mary B Martino, Hong Dang, Aiman Abzhanova, Jennifer M Lin, Emily A Hull-Ryde, Allison S Volmer, Scott H Randell, Alessandra Livraghi-Butrico, Yingfeng Deng, Philipp E Scherer, Barry R Stripp, Wanda K O'Neal, Richard C Boucher.

   RATIONALE: The goal was to connect elements of IPF pathogenesis, including: chronic endoplasmic reticulum stress in respiratory epithelia associated with injury/inflammation and remodeling; distal airway mucus obstruction and honeycomb cyst formation with accumulation of MUC5B; and associations between IPF risk and polymorphisms in the MUC5B promoter.
OBJECTIVES: Test whether the ER stress sensor protein ER-to-nucleus signaling 2 (ERN2) and its downstream effector, the spliced form of x-box binding protein 1 (XBP1S), regulate MUC5B expression and differentially activate the MUC5B promoter variant in respiratory epithelia.
METHODS AND MEASUREMENTS: Primary human airway epithelia (HAE), transgenic mouse models, human IPF lung tissues, and cell lines expressing XBP1S and MUC5B promoters were used to explore relationships between the ERN2/XBP1S pathway and MUC5B. An inhibitor of the pathway, KIRA6, and XBP1 CRISPR-Cas9 were used in HAE to explore therapeutic potential.
RESULTS: ERN2 regulated both MUC5B and MUC5AC mRNAs. Downstream XBP1S selectively promoted MUC5B expression in vitro and in distal murine airway epithelia in vivo. XBP1S bound to the proximal region of the MUC5B promoter and differentially up-regulated MUC5B expression in the context of the MUC5B promoter rs35705950 variant. High levels of ERN2 and XBP1S were associated with excessive MUC5B mRNAs in distal airways of human IPF lungs. Cytokine-induced MUC5B expression in HAE was inhibited by KIRA6 and XBP1 CRISPR-Cas9.
CONCLUSION: A positive feedback bistable ERN2-XBP1S pathway regulates MUC5B-dominated mucus obstruction in IPF, providing a UPR-dependent mechanism linking the MUC5B promoter rs35705950 polymorphism with IPF pathogenesis. Inhibiting ERN2-dependent pathways/elements may provide a therapeutic option for IPF.

Keywords:  MUC5B, IPF, airway epithelia

DOI:  https://doi.org/10.1164/rccm.201810-1972OC
Life Sci. 2019 Apr 09. pii: S0024-3205(19)30272-3. [Epub ahead of print]

GRP78: A cell's response to stress.

Ibrahim M Ibrahim, Doaa H Abdelmalek, Abdo A Elfiky.

   BACKGROUND: Glucose-Regulated Protein 78 (GRP78) is a chaperone heat shock protein that has been intensely studied in the last two decades. GRP78 is the master of the unfolded protein response (UBR) in the Endoplasmic Reticulum (ER) in normal cells. GRP78 force the unfolded proteins to refold or degrade using cellular degradation mechanisms.
SCOPE: Under stress, the overexpression of GRP78 on the cell membrane mediates the vast amount of disordered proteins. Unfortunately, this makes it a tool for pathogens (bacterial, fungal and viral) to enter the cell and to start different pathways leading to pathogenesis. Additionally, GRP78 is overexpressed on the membranes of various cancer cells and increase the aggressiveness of the disease.
MAJOR CONCLUSIONS: The current review summarizes structure, function, and different mechanisms GRP78 mediate in response to normal or stress conditions.
GENERAL SIGNIFICANCE: GRP78 targeting and possible inhibition mechanisms are also covered in the present review aiming to prevent the virulence of pathogens and cancer.

Keywords:  GRP78; HSP70; Heat shock proteins; Membrane receptors; Stress; Unfolded protein response

DOI:  https://doi.org/10.1016/j.lfs.2019.04.022
Am J Physiol Endocrinol Metab. 2019 Apr 09.

C/EBPβ mediates palmitate-induced musclin expression via the regulation of PERK/ATF4 pathways in myotubes.

Qian Guo, Hailong Hu, Xiaohuan Liu, DaQian Yang, Yao Yin, Boya Zhang, Hongjuan He, Yuri Oh, Qiong Wu, Chuanpeng Liu, Ning Gu.

  Musclin is a muscle-secreted cytokine that disrupts glucose uptake and glycogen synthesis in type 2 diabetes. The purpose of this study was to investigate the mechanisms responsible for the regulation of musclin gene expression in response to treatment with palmitate. RNA sequencing results showed that biological processes activated by palmitate are mainly enriched in endoplasmic reticulum (ER) stress. The protein kinase RNA-like ER kinase (PERK) signaling pathway is involved in the regulation of musclin expression induced by palmitate. Chromatin immunoprecipitation data showed that activating transcription factor 4 (ATF4) - downstream of PERK - bound to the promoter of the C/EBPβ gene. Notably, C/EBPβ also contains a binding site in the region -94~-52 of the musclin gene promoter. Knockdown or knockout of PERK and ATF4 using short hairpin RNA or CRISPR-Cas9 decreased the expression of C/EBPβ and musclin induced by palmitate. Furthermore, knockdown and knockout of C/EBPβ alleviated the high expression of musclin in response to treatment with palmitate. Moreover, CRISPR-Cas9 knockout of the region -94~-52 in which C/EBPβ binds to the promoter of musclin abrogated the induction of high musclin expression caused by palmitate. Collectively, these findings suggest that treatment with palmitate activates the PERK/ATF4 signaling pathway, which in turn increases the expression of C/EBPβ. C/EBPβ binds directly to the promoter of the musclin gene and upregulates its expression.

Keywords:  C/EBPβ; Musclin; PERK; Palmitate; Unfolded protein response (UPR)

DOI:  https://doi.org/10.1152/ajpendo.00478.2018
Elife. 2019 Apr 11. pii: e44425. [Epub ahead of print]8

Endoplasmic reticulum-associated SKN-1A/Nrf1 mediates a cytoplasmic unfolded protein response and promotes longevity.

Nicolas J Lehrbach, Gary Ruvkun.

  Unfolded protein responses (UPRs) safeguard cellular function during proteotoxic stress and aging. In a previous paper (Lehrbach and Ruvkun, 2016) we showed that the ER-associated SKN-1A/Nrf1 transcription factor activates proteasome subunit expression in response to proteasome dysfunction, but it was not established whether SKN-1A/Nrf1 adjusts proteasome capacity in response to other proteotoxic insults. Here, we reveal that misfolded endogenous proteins and the human amyloid beta peptide trigger activation of proteasome subunit expression by SKN-1A/Nrf1. SKN-1A activation is protective against age-dependent defects caused by accumulation of misfolded and aggregation-prone proteins. In a C. elegans Alzheimer's disease model, SKN-1A/Nrf1 slows accumulation of the amyloid beta peptide and delays adult-onset cellular dysfunction. Our results indicate that SKN-1A surveys cellular protein folding and adjusts proteasome capacity to meet the demands of protein quality control pathways, revealing a new arm of the cytosolic UPR. This regulatory axis is critical for healthy aging and may be a target for therapeutic modulation of human aging and age-related disease.

Keywords:  C. elegans; NFE2L1; SKN-1; UPR; aging; cell biology; genetics; genomics; proteasome; protein quality control

DOI:  https://doi.org/10.7554/eLife.44425
Front Immunol. 2019 ;10 506

Ablation of the Chaperone Protein ERdj5 Results in a Sjögren's Syndrome-Like Phenotype in Mice, Consistent With an Upregulated Unfolded Protein Response in Human Patients.

Eirini Apostolou, Petros Moustardas, Takao Iwawaki, Athanasios G Tzioufas, Giannis Spyrou.

  Objective: Sjögren's syndrome (SS) is a chronic autoimmune disorder that affects mainly the exocrine glands. Endoplasmic reticulum (ER) stress proteins have been suggested to participate in autoimmune and inflammatory responses, either acting as autoantigens, or by modulating factors of inflammation. The chaperone protein ERdj5 is an ER-resident disulfide reductase, required for the translocation of misfolded proteins during ER-associated protein degradation. In this study we investigated the role of ERdj5 in the salivary glands (SGs), in association with inflammation and autoimmunity. Methods: In situ expression of ERdj5 and XBP1 activation were studied immunohistochemically in minor SG tissues from primary SS patients and non-SS sicca-complaining controls. We used the mouse model of ERdj5 ablation and characterized its features: Histopathological, serological (antinuclear antibodies and cytokine levels), and functional (saliva flow rate). Results: ERdj5 was highly expressed in the minor SGs of SS patients, with stain intensity correlated to inflammatory lesion severity and anti-SSA/Ro positivity. Moreover, SS patients demonstrated higher XBP1 activation within the SGs. Remarkably, ablation of ERdj5 in mice conveyed many of the cardinal features of SS, like spontaneous inflammation in SGs with infiltrating T and B lymphocytes, distinct cytokine signature, excessive cell death, reduced saliva flow, and production of anti-SSA/Ro and anti-SSB/La autoantibodies. Notably, these features were more pronounced in female mice. Conclusions: Our findings suggest a critical connection between the function of the ER chaperone protein ERdj5 and autoimmune inflammatory responses in the SGs and provide evidence for a new, potent animal model of SS.

Keywords:  ER-stress; ERdj5; Sjögren's syndrome; UPR; XBP1; autoimmunity; salivary gland

DOI:  https://doi.org/10.3389/fimmu.2019.00506