Understanding the Unfolded Protein Response in the Pathogenesis of Asthma

Pathinayake, Prabuddha S; Hsu, Alan; Waters, Donna; Hansbro, Philip M.; Wood, Lisa G.; Wark, Peter

doi:10.3389/fimmu.2018.00175

Cited by 45 publications

(54 citation statements)

References 140 publications

(141 reference statements)

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“…ER stress has been shown to be induced by the CoV spike protein (Versteeg et al, 2007). ER-UPR features three main pathways, PERK-Erk-CHOP pathway that modulates apoptosis, ATF6 that regulates protein folding, and the IRE1 -TRAF2 pathway that promotes NF-κB and p38 activation (Pathinayake et al, 2018).…”

Section: Cov2-s1-mediated Nf-κb Activation Is Dependent On S1-ace2 Inmentioning

confidence: 99%

SARS-CoV-2 Spike protein promotes hyper-inflammatory response that can be ameliorated by Spike-antagonistic peptide and FDA-approved ER stress and MAP kinase inhibitorsin vitro

Hsu

Wang

Reid

et al. 2020

Preprint

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SARS-CoV-2 infection causes an inflammatory cytokine storm and acute lung injury. Currently there are no effective antiviral and/or anti-inflammatory therapies. Here we demonstrate that 2019 SARS-CoV-2 spike protein subunit 1 (CoV2-S1) induces high levels of NF-κB activations, production of pro-inflammatory cytokines and mild epithelial damage, in human bronchial epithelial cells. CoV2-S1-induced NF-κB activation requires S1 interaction with human ACE2 receptor and early activation of endoplasmic reticulum (ER) stress, and associated unfolded protein response (UPR), and MAP kinase signalling pathways. We developed an antagonistic peptide that inhibits S1-ACE2 interaction and CoV2-S1-induced productions of pro-inflammatory cytokines. The existing FDA-approved ER stress inhibitor, 4-phenylburic acid (4-PBA), and MAP kinase inhibitors, trametinib and ulixertinib, ameliorated CoV2-S1-induced inflammation and epithelial damage. These novel data highlight the potentials of peptide-based antivirals for novel ACE2-utilising CoVs, while repurposing existing drugs may be used as treatments to dampen elevated inflammation and lung injury mediated by SARS-CoV-2.

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Section: Cov2-s1-mediated Nf-κb Activation Is Dependent On S1-ace2 Inmentioning

confidence: 99%

SARS-CoV-2 Spike protein promotes hyper-inflammatory response that can be ameliorated by Spike-antagonistic peptide and FDA-approved ER stress and MAP kinase inhibitorsin vitro

Hsu

Wang

Reid

et al. 2020

Preprint

Self Cite

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“…To date no other study has explored whether inflammation induces ER stress in hASM and whether an ER stress response in hASM cells from asthmatic patients exists and/or is affected by inflammation. A few studies suggest that the ER stress response is exaggerated in airway epithelial cells or immune cells in the context of asthma (Kim and Lee, 2015;Jeong et al, 2017;Pathinayake et al, 2018). In a mouse model of asthma, chemical chaperones have been used to reduce the ER stress response and attenuate airway hyperresponsiveness (Makhija et al, 2014;Miller et al, 2014;Kim and Lee, 2015;Siddesha et al, 2016).…”

Section: Inflammation and Er Stress In Human Asmmentioning

confidence: 99%

Endoplasmic Reticulum Stress and Mitochondrial Function in Airway Smooth Muscle

Delmotte

Sieck

2020

Front. Cell Dev. Biol.

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Inflammatory airway diseases such as asthma affect more than 300 million people worldwide. Inflammation triggers pathophysiology via such as tumor necrosis factor α (TNFα) and interleukins (e.g., IL-13). Hypercontraction of airway smooth muscle (ASM) and ASM cell proliferation are major contributors to the exaggerated airway narrowing that occurs during agonist stimulation. An emergent theme in this context is the role of inflammationinduced endoplasmic reticulum (ER) stress and altered mitochondrial function including an increase in the formation of reactive oxygen species (ROS). This may establish a vicious cycle as excess ROS generation leads to further ER stress. Yet, it is unclear whether inflammation-induced ROS is the major mechanism leading to ER stress or the consequence of ER stress. In various diseases, inflammation leads to an increase in mitochondrial fission (fragmentation), associated with reduced levels of mitochondrial fusion proteins, such as mitofusin 2 (Mfn2). Mitochondrial fragmentation may be a homeostatic response since it is generally coupled with mitochondrial biogenesis and mitochondrial volume density thereby reducing demand on individual mitochondrion. ER stress is triggered by the accumulation of unfolded proteins, which induces a homeostatic response to alter protein balance via effects on protein synthesis and degradation. In addition, the ER stress response promotes protein folding via increased expression of molecular chaperone proteins. Reduced Mfn2 and altered mitochondrial dynamics may not only be downstream to ER stress but also upstream such that a reduction in Mfn2 triggers further ER stress. In this review, we summarize the current understanding of the link between inflammation-induced ER stress and mitochondrial function and the role played in the pathophysiology of inflammatory airway diseases.

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“…Inflammatory insults, such as OVA or IL-33, lead to massive increases in Muc5ac protein synthesis, ER stress (31,59), and oxidative stress (8,60). Our findings suggest that airway mucous cells utilize the autophagosome-lysosome protein degradation system to break down mucin proteins to restore cellular homeostasis after the inflammatory insult is over.…”

Section: Discussionmentioning

confidence: 78%

Mucin granules are degraded in the autophagosome-lysosome pathway as a means of resolving airway mucous cell metaplasia

Sweeter

Kudrna

Hunt

et al. 2020

Preprint

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Exacerbations of muco-obstructive airway diseases such as COPD and asthma are associated with epithelial changes termed mucous cell metaplasia (MCM). The molecular pathways triggering MCM have been identified; however, the factors that regulate resolution are less well understood. We hypothesized that the autophagosome-lysosome pathway is required for resolution of MCM by degrading cytoplasmic mucins. We found increased intracellular levels of Muc5ac and Muc5b in autophagy-deficient mice. This difference was not due to defective mucin secretion. Instead, we found that Lamp1-labeled lysosomes surrounded mucin granules of mucous cells indicating that granules were being degraded. Using a model of resolution of mucous cell metaplasia in mice, we found increased lysosomal proteolytic activity that peaked in the days after inflammation. Autophagy-deficient mice had persistent accumulation of mucin granules that failed to decline due to reduced mucin degradation. We applied these findings in vitro to human airway epithelial cells (AECs). Activation of autophagy by mTOR inhibition led to degradation of mucin granules in AECs. Our findings indicate that during peak and resolution phases of MCM, mucin granules can be degraded by autophagy. The addition of mucin degradation to the existing paradigm of production and secretion may more fully explain how the secretory cells handle excess amounts of cytoplasmic mucin and offers a therapeutic target to speed resolution of MCM in airway disease exacerbations. Introduction:Mammalian cells utilize two primary degradation systems to recycle proteins: the proteasome and the autophagosome-lysosome pathways. While there is some overlap, these pathways are largely independently regulated and serve different functions(1). These protein degradation systems are necessary for the cell to balance metabolic demands by recycling proteins to amino acids for new synthesis. The autophagosome-lysosome pathway is highly conserved across species(2, 3). It can be utilized in bulk protein breakdown (macro-autophagy or referred to as autophagy) in response to nutrient demands for new amino acids. Cells can also utilize chaperone-mediated autophagy that utilizes a specific amino acid motif targeted by cytoplasmic chaperones that bypass the autophagosome and directly insert proteins in the lysosome for degradation. Finally, cells can utilize selective autophagy by targeting proteins, protein aggregates, and organelles including mitochondria(4, 5) and even cilia components(6) to the autophagosome for degradation in the lysosome. We (7,8), and others(9-13), have observed that autophagy markers are increased in models of human airway disease, and in asthma and COPD airways. This led us to infer that autophagy played a key role in the response to airway inflammation in the epithelium.Mucociliary clearance is a vital feature of innate immunity (14,15). There are two primary secretory mucins in the murine and human airways, MUC5B and MUC5AC, that provide the biophysical properties of mucous gel layer (16,17)...

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Understanding the Unfolded Protein Response in the Pathogenesis of Asthma

Cited by 45 publications

References 140 publications

SARS-CoV-2 Spike protein promotes hyper-inflammatory response that can be ameliorated by Spike-antagonistic peptide and FDA-approved ER stress and MAP kinase inhibitorsin vitro

SARS-CoV-2 Spike protein promotes hyper-inflammatory response that can be ameliorated by Spike-antagonistic peptide and FDA-approved ER stress and MAP kinase inhibitorsin vitro

Endoplasmic Reticulum Stress and Mitochondrial Function in Airway Smooth Muscle

Mucin granules are degraded in the autophagosome-lysosome pathway as a means of resolving airway mucous cell metaplasia

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