Mechanisms Targeting the Unfolded Protein Response in Asthma

Dastghaib, Sanaz; Kumar, Priyam; Aftabi, Sajjad; Damera, Gautam; Dalvand, Azadeh; Sepanjnia, Adel; Kiumarsi, Mohammad; Aghanoori, Mohamad‐Reza; Sohal, Sukhwinder Singh; Ande, Sudharsana Rao; Alizadeh, Javad; Mokarram, Pooneh; Ghavami, Saeid; Sharma, Pawan; Zeki, Amir A.

doi:10.1165/rcmb.2019-0235tr

Cited by 24 publications

(17 citation statements)

References 113 publications

(143 reference statements)

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“…BiP is the upstream chaperon that inhibits PERK (protein kinase R (PKR)-like endoplasmic reticulum kinase), IRE1 (inositol-requiring enzyme 1), and ATF6 (activating transcription factor 6) chaperons via direct interaction in non-stressed conditions [ 20 , 46 , 47 ]. Therefore, BiP expression is representative of the overall activation of UPR and the potential involvement of all three arms of this pathway [ 48 ]. IRE1 has both kinase and RNAse activity, and its RNAse activity is responsible for the splicing of XBP1 into “spliced XPB1” (XBP1s) [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Autophagy, Apoptosis, the Unfolded Protein Response, and Lung Function in Idiopathic Pulmonary Fibrosis

Sharma

Alizadeh

Juarez

et al. 2021

Cells

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Autophagy, apoptosis, and the unfolded protein response (UPR) are fundamental biological processes essential for manifold cellular functions in health and disease. Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal pulmonary disorder associated with aging that has limited therapies, reflecting our incomplete understanding. We conducted an observational study linking molecular markers of cell stress response pathways (UPR: BiP, XBP1; apoptosis: cleaved caspase-3; autophagy: LC3β) in lung tissues from IPF patients and correlated the expression of these protein markers to each subject’s lung function measures. We hypothesized that changes in lung tissue expression of apoptosis, autophagy, and UPR markers correlate with lung function deficits in IPF. The cell stress markers BiP, XBP1, LC3β puncta, and cleaved caspase-3 were found to be elevated in IPF lungs compared to non-IPF lungs, and, further, BiP and cleaved caspase-3 co-localized in IPF lungs. Considering lung function independently, we observed that increased XBP1, BiP, and cleaved caspase-3 were each associated with reduced lung function (FEV1, FVC, TLC, RV). However, increased lung tissue expression of LC3β puncta was significantly associated with increased diffusion capacity (DLCO), an indicator of alveolar–capillary membrane function. Similarly, the co-localization of UPR (XBP1, BiP) and autophagy (LC3β puncta) markers was positively correlated with increased lung function (FEV1, FVC, TLC, DLCO). However, the presence of LC3β puncta can indicate either autophagy flux inhibition or activation. While the nature of our observational cross-sectional study design does not allow conclusions regarding causal links between increased expression of these cell stress markers, lung fibrosis, and lung function decline, it does provide some insights that are hypothesis-generating and suggests that within the milieu of active UPR, changes in autophagy flux may play an important role in determining lung function. Further research is necessary to investigate the mechanisms linking UPR and autophagy in IPF and how an imbalance in these cell stress pathways can lead to progressive fibrosis and loss of lung function. We conclude by presenting five testable hypotheses that build on the research presented here. Such an understanding could eventually lead to the development of much-needed therapies for IPF.

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Section: Discussionmentioning

confidence: 99%

Autophagy, Apoptosis, the Unfolded Protein Response, and Lung Function in Idiopathic Pulmonary Fibrosis

Sharma

Alizadeh

Juarez

et al. 2021

Cells

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“…Two main models for UPR activation have been discussed most frequently. The first model is similar to that of the heat shock response pathway and relies on the availability and regulated binding of the chaperone BiP [2,3,12,13]. BiP homeostatically binds to UPR sensor proteins to prevent their oligomerization, which is interrupted during ER stress.…”

Section: Unfolded Protein Responsementioning

confidence: 99%

“…A disturbance in the synthesis, secretion, or destruction of proteins may lead to the accumulation of non-folded or mis-folded proteins within the ER, disrupting its normal function [1,2]. Such an impairment of ER homeostasis is referred to as ER stress, which plays a significant role in cellular survival and function [3].…”

Section: Introductionmentioning

confidence: 99%

The ER Stress/UPR Axis in Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis

Aghaei

Dastghaib

Aftabi

et al. 2020

Life

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Cellular protein homeostasis in the lungs is constantly disrupted by recurrent exposure to various external and internal stressors, which may cause considerable protein secretion pressure on the endoplasmic reticulum (ER), resulting in the survival and differentiation of these cell types to meet the increased functional demands. Cells are able to induce a highly conserved adaptive mechanism, known as the unfolded protein response (UPR), to manage such stresses. UPR dysregulation and ER stress are involved in numerous human illnesses, such as metabolic syndrome, fibrotic diseases, and neurodegeneration, and cancer. Therefore, effective and specific compounds targeting the UPR pathway are being considered as potential therapies. This review focuses on the impact of both external and internal stressors on the ER in idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) and discusses the role of the UPR signaling pathway activation in the control of cellular damage and specifically highlights the potential involvement of non-coding RNAs in COPD. Summaries of pathogenic mechanisms associated with the ER stress/UPR axis contributing to IPF and COPD, and promising pharmacological intervention strategies, are also presented.

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“…Endoplasmic reticulum (ER) stress is involved in maintaining cell homeostasis, lipid synthesis, protein folding, translocation, and post-translational modifications. Various stresses, including hypoxia, starvation, pH changes, calcium depletion, and viral infections, can interfere with the ER environment [ 14 ]. Viral infection and toxicity may cause ER stress through the use of the ER membrane, aggregation of misfolded proteins, calcium imbalances due to the formation of viroporins, and destruction of the ER membrane while the virions are embedding [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Autophagy, Unfolded Protein Response, and Neuropilin-1 Cross-Talk in SARS-CoV-2 Infection: What Can Be Learned from Other Coronaviruses

Siri

Dastghaib

Zamani

et al. 2021

IJMS

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The COVID-19 pandemic is caused by the 2019–nCoV/SARS-CoV-2 virus. This severe acute respiratory syndrome is currently a global health emergency and needs much effort to generate an urgent practical treatment to reduce COVID-19 complications and mortality in humans. Viral infection activates various cellular responses in infected cells, including cellular stress responses such as unfolded protein response (UPR) and autophagy, following the inhibition of mTOR. Both UPR and autophagy mechanisms are involved in cellular and tissue homeostasis, apoptosis, innate immunity modulation, and clearance of pathogens such as viral particles. However, during an evolutionary arms race, viruses gain the ability to subvert autophagy and UPR for their benefit. SARS-CoV-2 can enter host cells through binding to cell surface receptors, including angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP1). ACE2 blockage increases autophagy through mTOR inhibition, leading to gastrointestinal complications during SARS-CoV-2 virus infection. NRP1 is also regulated by the mTOR pathway. An increased NRP1 can enhance the susceptibility of immune system dendritic cells (DCs) to SARS-CoV-2 and induce cytokine storm, which is related to high COVID-19 mortality. Therefore, signaling pathways such as mTOR, UPR, and autophagy may be potential therapeutic targets for COVID-19. Hence, extensive investigations are required to confirm these potentials. Since there is currently no specific treatment for COVID-19 infection, we sought to review and discuss the important roles of autophagy, UPR, and mTOR mechanisms in the regulation of cellular responses to coronavirus infection to help identify new antiviral modalities against SARS-CoV-2 virus.

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Mechanisms Targeting the Unfolded Protein Response in Asthma

Cited by 24 publications

References 113 publications

Autophagy, Apoptosis, the Unfolded Protein Response, and Lung Function in Idiopathic Pulmonary Fibrosis

Autophagy, Apoptosis, the Unfolded Protein Response, and Lung Function in Idiopathic Pulmonary Fibrosis

The ER Stress/UPR Axis in Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis

Autophagy, Unfolded Protein Response, and Neuropilin-1 Cross-Talk in SARS-CoV-2 Infection: What Can Be Learned from Other Coronaviruses

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