The IRE1-XBP1 Branch of the Unfolded Protein Response Underpins Cytokine Induction and Viral Replication in SARS-CoV-2 Infection DOI Creative Commons

José Javier Fernández Rodríguez

Published: Jan. 1, 2022

The endoplasmic reticulum (ER) is an intracellular organelle involved, among other functions, in the synthesis and secretion of proteins.These processes are tightly regulated to control quality protein secretion.However, excessive load can perturb ER homeostasis leading accumulation misfolded proteins resulting activation unfolded response (UPR).Viral infections including SARS-CoV-2, as a positive single stranded RNA (ssRNA) virus, might cause stress because exploitation host machinery for viral replication.Endosomal Tolllike receptors (TLR)7 TLR8 sense ssRNA associated SARS-CoV-2 virus.Recognition by its cognate drives transcription translation pro-inflammatory genes, which after release into systemic circulation, may team up with UPR ignite cytokine storm (CS) or sepsis observed severe forms disease.Our approach aimed understand connection between infection UPR, focusing on role factor spliced XBP1 replication overproduction.The study encompasses: i) analysis nasopharyngeal swabs samples bronchiolo-alveolar aspirates patients undergoing mechanical ventilation due pneumonia hospitalized at Internal Care Unit (ICU), ii) experiments monocyte derived dendritic cells (MDDCs) stimulated via TLR7/8, iii) studies vivo iv) impact modulation during cycle human epithelial infected different variants concern (VOCs).Taken collectively, has disclosed that IRE1α-XBP1 branch host-dependent involved pathogenesis. Indexenergetic metabolism process induction.These results were published Cell Reports.Due global COVID-19 pandemic expertise our laboratory innate immunity inflammation, we had unique chance apply major public health challenge caused infection.Recent (UPR) plays production inflammatory [7,8].The system been found be robust enhancer proinflammatory IL-23 fungal infections, reported [6].This background paved way address pathophysiological mechanisms underlying clinical setting fever, immunosuppression, aggravates course .Our working hypothesis was sXBP1 could pathogenesis multiorgan failure characteristic disease.For purpose, adapted portion work infection, special emphasis arm induction storm. II. Introductioncells from nasal exudates patients, transcripts have also neutrophiles macrophages [32].Plasmacytoid (pDCs) infiltrating lung activate through .This milieu optimal produce cytokines chemokines paves attraction T niche enhance recruiting IFN-γ [34].Although primary goal these responses blockade proliferation hyperactivation immune induce unintended CS increases disease severity.SARS-CoV-2 RNA, reports showing loss-of-function Xchromosomal TLR7 driving impaired type I II IFN associate young [72].The purpose this addressing whether TLR7/8 engagement contribute disease, given dysregulated TLR lead persistent inflammation tissue damage [73-75] TLRs recognize life SARS-CoV-2.In addition, involvement postulated target potential therapeutics [76].

Language: Английский

Human Betacoronavirus OC43 Interferes with the Integrated Stress Response Pathway in Infected Cells DOI Creative Commons
Stacia M. Dolliver,

Caleb Galbraith,

Denys A. Khaperskyy

et al.

Viruses, Journal Year: 2024, Volume and Issue: 16(2), P. 212 - 212

Published: Jan. 31, 2024

Viruses evolve many strategies to ensure the efficient synthesis of their proteins. One such strategy is inhibition integrated stress response—the mechanism through which infected cells arrest translation phosphorylation alpha subunit eukaryotic initiation factor 2 (eIF2α). We have recently shown that human common cold betacoronavirus OC43 actively inhibits eIF2α in response sodium arsenite, a potent inducer oxidative stress. In this work, we examined modulation responses by and demonstrated negative feedback regulator GADD34 strongly induced cells. However, upregulation expression was independent from activation not required for virus-infected Our work reveals complex interplay between coronavirus response, viral protein ensured but loop disrupted.

Language: Английский

Citations

4
Insights into the Activation of Unfolded Protein Response Mechanism during Coronavirus Infection DOI Creative Commons
Panagiotis Κeramidas,

Maria Pitou,

Eleni Papachristou

et al.

Current Issues in Molecular Biology, Journal Year: 2024, Volume and Issue: 46(5), P. 4286 - 4308

Published: May 5, 2024

Coronaviruses represent a significant class of viruses that affect both animals and humans. Their replication cycle is strongly associated with the endoplasmic reticulum (ER), which, upon virus invasion, triggers ER stress responses. The activation unfolded protein response (UPR) within infected cells performed from three transmembrane receptors, IRE1, PERK, ATF6, results in reduction production, boost ER’s ability to fold proteins properly, initiation ER-associated degradation (ERAD) remove misfolded or proteins. However, cases prolonged severe stress, UPR can also instigate apoptotic cell death inflammation. Herein, we discuss ER-triggered host responses after coronavirus infection, as well pharmaceutical targeting potential antiviral strategy.

Language: Английский

Citations

4
Spike protein-related proteinopathies: a focus on the neurological side of spikeopathies DOI Creative Commons
Andreas Posa

Annals of Anatomy - Anatomischer Anzeiger, Journal Year: 2025, Volume and Issue: unknown, P. 152662 - 152662

Published: April 1, 2025

Language: Английский

Citations

0
Betacoronaviruses Differentially Activate the Integrated Stress Response to Optimize Viral Replication in Lung-Derived Cell Lines DOI Creative Commons
David M. Renner, Nicholas A. Parenti, Nicole Bracci

et al.

Viruses, Journal Year: 2025, Volume and Issue: 17(1), P. 120 - 120

Published: Jan. 16, 2025

The betacoronavirus genus contains five of the seven human coronaviruses, making it a particularly critical area research to prepare for future viral emergence. We utilized three betacoronaviruses, one from each subgenus—HCoV-OC43 (embecovirus), SARS-CoV-2 (sarbecovirus), and MERS-CoV (merbecovirus)—, study interactions with PKR-like ER kinase (PERK) pathway integrated stress response (ISR)/unfolded protein (UPR). PERK becomes activated by an abundance unfolded proteins within endoplasmic reticulum (ER), leading phosphorylation eIF2α translational attenuation. demonstrate that MERS-CoV, HCoV-OC43, all activate induce responses downstream p-eIF2α, while only induces detectable p-eIF2α during infection. Using small molecule inhibitor dephosphorylation, we provide evidence HCoV-OC43 maximize replication through dephosphorylation. Interestingly, genetic ablation growth arrest DNA damage-inducible (GADD34) expression, inducible phosphatase 1 (PP1)-interacting partner targeting did not significantly alter or replication, siRNA knockdown constitutive PP1 partner, repressor (CReP), dramatically reduced replication. Combining GADD34 knockout CReP had maximum impact on was unaffected. Overall, conclude dephosphorylation is efficient production SARS-CoV-2, however, appears be insensitive and, infection, may even downregulate limit host translation.

Language: Английский

Citations

0
Modulation of endoplasmic reticulum stress response pathways by respiratory viruses DOI
Kyle L. Macauslane, Cassandra L. Pegg, Kirsty R. Short

et al.

Critical Reviews in Microbiology, Journal Year: 2023, Volume and Issue: 50(5), P. 750 - 768

Published: Nov. 7, 2023

Acute respiratory infections (ARIs) are amongst the leading causes of death and disability, greatest burden disease impacts children, pregnant women, elderly. Respiratory viruses account for majority ARIs. The unfolded protein response (UPR) is a host homeostatic defence mechanism primarily activated in to aberrant endoplasmic reticulum (ER) resident accumulation cell stresses including viral infection. UPR has been implicated pathogenesis several diseases, as system particularly vulnerable chronic acute activation ER stress pathway. Many therefore employ strategies modulate during infection, with varying effects on pathogens. Here, we review specific means by which affect UPR, association high production glycoproteins, impact subversion replication pathogenesis. We further common co-morbidities ARIs discuss therapeutic potential modulating virally induced diseases.

Language: Английский

Citations

9
The IRE1α-XBP1 arm of the unfolded protein response is a host factor activated in SARS-CoV-2 infection DOI
José Javier Fernández, Arturo Marín, Romel Rosales

et al.

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Journal Year: 2024, Volume and Issue: 1870(5), P. 167193 - 167193

Published: April 21, 2024

Language: Английский

Citations

3
Nanoscopic Elucidation of Spontaneous Self-Assembly of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Open Reading Frame 6 (ORF6) Protein DOI Creative Commons
Goro Nishide, Keesiang Lim, M. Tamura

et al.

The Journal of Physical Chemistry Letters, Journal Year: 2023, Volume and Issue: 14(38), P. 8385 - 8396

Published: Sept. 14, 2023

Open reading frame 6 (ORF6), the accessory protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that suppresses host type-I interferon signaling, possesses amyloidogenic sequences. ORF6 peptides self-assemble to produce cytotoxic amyloid fibrils. Currently, molecular properties remain elusive. Here, we investigate structural dynamics full-length in a near-physiological environment using high-speed atomic force microscopy. oligomers were ellipsoidal and readily assembled into protofilaments either circular or linear pattern. The formation was enhanced at higher temperatures on lipid substrate. filaments sensitive aliphatic alcohols, urea, SDS, indicating predominantly maintained by hydrophobic interactions. In summary, self-assembly could be necessary sequester factors causes collateral damage cells via aggregates. Nanoscopic imaging unveiled innate behavior provides insight drug repurposing treat amyloid-related disease 2019 complications.

Language: Английский

Citations

7
Taohong Siwu decoction alleviates cognitive impairment by suppressing endoplasmic reticulum stress and apoptosis signaling pathway in vascular dementia rats DOI

Ling-Ling Fan,

Fang Hao, Jiayi Zheng

et al.

Journal of Ethnopharmacology, Journal Year: 2024, Volume and Issue: 333, P. 118407 - 118407

Published: May 31, 2024

Language: Английский

Citations

2
The unfolded protein response components IRE1α and XBP1 promote human coronavirus infection DOI Creative Commons
Jessica M. Oda,

Andreas B. den Hartigh,

Shoen M. Jackson

et al.

mBio, Journal Year: 2023, Volume and Issue: unknown

Published: June 12, 2023

The cellular processes that support human coronavirus replication and contribute to the pathogenesis of severe disease remain incompletely understood. Many viruses, including coronaviruses, cause endoplasmic reticulum (ER) stress during infection. IRE1α is a component response ER initiates non-conventional splicing XBP1 mRNA. Spliced encodes transcription factor induces expression ER-related targets. Activation IRE1α-XBP1 pathway occurs in association with risk factors for In this study, we found coronaviruses HCoV-OC43 (human OC43) SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) both robustly activate branch unfolded protein cultured cells. Using nuclease inhibitors genetic knockdown XBP1, these host are required optimal viruses. Our data suggest supports infection downstream initial viral attachment entry. addition, stress-inducing conditions sufficient enhance replication. Furthermore, markedly increased circulation patients 2019 (COVID-19). Together, results demonstrate importance IMPORTANCE There critical need understand co-opted replication, an emphasis on identifying mechanisms underlying potential therapeutic Here, proteins robust by HCoV-OC43. participate activated predispose COVID-19. We enhanced exogenous activation, evidence humans

Language: Английский

Citations

6
Improved Culture Methods for Human Coronaviruses HCoV‐OC43, HCoV‐229E, and HCoV‐NL63 DOI
Alejandra Fausto, Clayton J. Otter, Nicole Bracci

et al.

Current Protocols, Journal Year: 2023, Volume and Issue: 3(10)

Published: Oct. 1, 2023

Abstract HCoV‐OC43, HCoV‐229E, HCoV‐NL63, and HCoV‐HKU1 are four of the seven known human coronaviruses (HCoVs) and, unlike highly pathogenic SARS‐CoV, MERS‐CoV, SARS‐CoV‐2, these so‐called seasonal HCoVs generally cause mild upper‐respiratory‐tract illness. As Biosafety Level 2 (BSL‐2) pathogens, more accessible can be used as surrogates for studying HCoVs. However, scientists have many years found difficult to study because lack a universal culture system inability typical methods yield high‐titer infectious stocks. We developed assays grow quantify virus viral RNA ‐229E, ‐NL63. identified which immortalized cell lines should optimize replication ‐NL63 in order generate high titers (Vero E6, Huh‐7, LLC‐MK2 cells, respectively). Here we present protocols improved propagation quantification each HCoV. © 2023 Wiley Periodicals LLC. Basic Protocol 1 : Growth Quantification HCoV by plaque assay 3 products 4 Concentrating via ultracentrifugation This article was corrected on 20 March 2024. See end full text details.

Language: Английский

Citations

5