scholarly journals Unfolded Protein Response as a Therapeutic Target in Cardiovascular Disease

2019 ◽  
Vol 19 (21) ◽  
pp. 1902-1917 ◽  
Author(s):  
Guangyu Zhang ◽  
Xiaoding Wang ◽  
Thomas G. Gillette ◽  
Yingfeng Deng ◽  
Zhao V. Wang
Keyword(s):  
Cardiovascular Disease ◽  
Protein Folding ◽  
Unfolded Protein Response ◽  
Protein Translation ◽  
Ample Evidence ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
Chronic Disturbance ◽  
The Unfolded Protein Response ◽  
Protein Response

Cardiovascular disease is the leading cause of death worldwide. Despite overwhelming socioeconomic impact and mounting clinical needs, our understanding of the underlying pathophysiology remains incomplete. Multiple forms of cardiovascular disease involve an acute or chronic disturbance in cardiac myocytes, which may lead to potent activation of the Unfolded Protein Response (UPR), a cellular adaptive reaction to accommodate protein-folding stress. Accumulation of unfolded or misfolded proteins in the Endoplasmic Reticulum (ER) elicits three signaling branches of the UPR, which otherwise remain quiescent. This ER stress response then transiently suppresses global protein translation, augments production of protein-folding chaperones, and enhances ER-associated protein degradation, with an aim to restore cellular homeostasis. Ample evidence has established that the UPR is strongly induced in heart disease. Recently, the mechanisms of action and multiple pharmacological means to favorably modulate the UPR are emerging to curb the initiation and progression of cardiovascular disease. Here, we review the current understanding of the UPR in cardiovascular disease and discuss existing therapeutic explorations and future directions.

scholarly journals The stress-induced protein NUPR1 orchestrates protein translation during ER-stress by interacting with eIF2α

2020 ◽  
Author(s):  
Maria Teresa Borrello ◽  
Patricia Santofimia-Castaño ◽  
Marco Bocchio ◽  
Angela Listi ◽  
Nicolas Fraunhoffer ◽  
...  
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Protein Translation ◽  
Morphological Observation ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
General Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractNUPR1 is a stress response protein overexpressed upon cell injury in virtually all organs including the exocrine pancreas. Despite NUPR1’s well established role in the response to cell stress, the molecular and structural machineries triggered by NUPR1 activation remain largely unknown. In this study, we uncover an important role for NUPR1 in participating in the unfolded protein response pathway and the endoplasmic reticulum stress response. Biochemical results, confirmed by ultrastructural morphological observation, revealed alterations in the UPR in acinar cells of germline-deleted NUPR1 murine models, consistent with the inability to restore general protein translation. Bioinformatical analysis of NUPR1 interacting partners showed significant enrichment in translation initiation factors, including eukaryotic initiation factor (eIF) 2α. Co-immunoprecipitation and proximity ligation assays both confirmed interaction between NUPR1 and eIF2α and its phosphorylated form (p-eIF2α). Our. Moreover, our data also suggest loss of NUPR1 in cells results in maintained eIF2α phosphorylation and evaluation of nascent proteins by (peIF2α), and click chemistry revealed that NUPR1-depleted PANC-1 cells displayed a slower post stress protein translational recovery compared to wild-type. Combined, this data proposes a novel role for NUPR1 in the integrated stress response pathway, at least partially through promoting efficient PERK-branch activity and resolution through a unique interaction with eIF2α.SignificanceIn the pancreas, NUPR1 is required for a resolution of the ER stress response. During ER stress response, NUPR1 binds both eIF2α allowing for its dephosphorylation and restoration of new protein synthesis.HighlightsBiochemical analysis revealed a general reduction in the protein expression of downstream mediators of the unfolded protein response in the pancreas of mice lacking Nupr1. This finding suggests a novel role for NUPR1 in the UPR/ER stress response.Ultrastructural analysis of pancreata revealed reduced morphological alterations in tunicamycin-treated Nupr1-/- mice compared to Nupr1+/+ mice consistent with a maintained block in general protein translation.Co-immunoprecipitation of tagged NUPR1 confirmed a novel interaction with eIF2α. Depletion of NUPR1 prolonged phosphorylation of eIF2α, suggesting it may be involved in attenuation of the PERK branch of the UPR.NUPR1-depleted PANC-1 cells displayed a slower recovery of protein translation following UPR activation

scholarly journals HY5, a positive regulator of light signaling, negatively controls the unfolded protein response inArabidopsis

2017 ◽  
Vol 114 (8) ◽  
pp. 2084-2089 ◽  
Author(s):  
Ganesh M. Nawkar ◽  
Chang Ho Kang ◽  
Punyakishore Maibam ◽  
Joung Hun Park ◽  
Young Jun Jung ◽  
...  
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Molecular Mechanism ◽  
26S Proteasome ◽  
Light Signaling ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
The Unfolded Protein Response ◽  
Protein Response

Light influences essentially all aspects of plant growth and development. Integration of light signaling with different stress response results in improvement of plant survival rates in ever changing environmental conditions. Diverse environmental stresses affect the protein-folding capacity of the endoplasmic reticulum (ER), thus evoking ER stress in plants. Consequently, the unfolded protein response (UPR), in which a set of molecular chaperones is expressed, is initiated in the ER to alleviate this stress. Although its underlying molecular mechanism remains unknown, light is believed to be required for the ER stress response. In this study, we demonstrate that increasing light intensity elevates the ER stress sensitivity of plants. Moreover, mutation of the ELONGATED HYPOCOTYL 5 (HY5), a key component of light signaling, leads to tolerance to ER stress. This enhanced tolerance ofhy5plants can be attributed to higher expression of UPR genes. HY5 negatively regulates the UPR by competing with basic leucine zipper 28 (bZIP28) to bind to the G-box–like element present in the ER stress response element (ERSE). Furthermore, we found that HY5 undergoes 26S proteasome-mediated degradation under ER stress conditions. Conclusively, we propose a molecular mechanism of crosstalk between the UPR and light signaling, mediated by HY5, which positively mediates light signaling, but negatively regulates UPR gene expression.

scholarly journals MicroRNA-30c-2* limits expression of proadaptive factor XBP1 in the unfolded protein response

2012 ◽  
Vol 196 (6) ◽  
pp. 689-698 ◽  
Author(s):  
Andrew E. Byrd ◽  
Ileana V. Aragon ◽  
Joseph W. Brewer
Keyword(s):  
Unfolded Protein Response ◽  
Cell Fate ◽  
Translational Control ◽  
Secretory Pathway ◽  
Signaling System ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Secretory Capacity

Stress in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR), a multifaceted signaling system coordinating translational control and gene transcription to promote cellular adaptation and survival. Microribonucleic acids (RNAs; miRNAs), single-stranded RNAs that typically function as posttranscriptional modulators of gene activity, have been shown to inhibit translation of certain secretory pathway proteins during the UPR. However, it remains unclear whether miRNAs regulate UPR signaling effectors directly. In this paper, we report that a star strand miRNA, miR-30c-2* (recently designated miR-30c-2-3p), is induced by the protein kinase RNA activated–like ER kinase (PERK) pathway of the UPR and governs expression of XBP1 (X-box binding protein 1), a key transcription factor that augments secretory capacity and promotes cell survival in the adaptive UPR. These data provide the first link between an miRNA and direct regulation of the ER stress response and reveal a novel molecular mechanism by which the PERK pathway, via miR-30c-2*, influences the scale of XBP1-mediated gene expression and cell fate in the UPR.

scholarly journals COPII mitigates ER stress by promoting formation of ER whorls

Cell Research ◽  
2020 ◽  
Author(s):  
Fang Xu ◽  
Wanqing Du ◽  
Qin Zou ◽  
Yuting Wang ◽  
Xin Zhang ◽  
...  
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Protein Translation ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
Membrane Budding ◽  
Free Environment ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Whorls

Abstract Cells mitigate ER stress through the unfolded protein response (UPR). Here, we report formation of ER whorls as an effector mechanism of the ER stress response. We found that strong ER stress induces formation of ER whorls, which contain ER-resident proteins such as the Sec61 complex and PKR-like ER kinase (PERK). ER whorl formation is dependent on PERK kinase activity and is mediated by COPII machinery, which facilitates ER membrane budding to form tubular-vesicular ER whorl precursors. ER whorl precursors then go through Sec22b-mediated fusion to form ER whorls. We further show that ER whorls contribute to ER stress-induced translational inhibition by possibly modulating PERK activity and by sequestering translocons in a ribosome-free environment. We propose that formation of ER whorls reflects a new type of ER stress response that controls inhibition of protein translation.

scholarly journals The Unfolded Protein Response as a Guardian of the Secretory Pathway

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2965
Author(s):  
Toni Radanović ◽  
Robert Ernst
Keyword(s):  
Protein Folding ◽  
Unfolded Protein Response ◽  
Secretory Pathway ◽  
Unfolded Proteins ◽  
Storage Lipids ◽  
Unfolded Protein ◽  
Membrane Stiffness ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Membrane

The endoplasmic reticulum (ER) is the major site of membrane biogenesis in most eukaryotic cells. As the entry point to the secretory pathway, it handles more than 10,000 different secretory and membrane proteins. The insertion of proteins into the membrane, their folding, and ER exit are affected by the lipid composition of the ER membrane and its collective membrane stiffness. The ER is also a hotspot of lipid biosynthesis including sterols, glycerophospholipids, ceramides and neural storage lipids. The unfolded protein response (UPR) bears an evolutionary conserved, dual sensitivity to both protein-folding imbalances in the ER lumen and aberrant compositions of the ER membrane, referred to as lipid bilayer stress (LBS). Through transcriptional and non-transcriptional mechanisms, the UPR upregulates the protein folding capacity of the ER and balances the production of proteins and lipids to maintain a functional secretory pathway. In this review, we discuss how UPR transducers sense unfolded proteins and LBS with a particular focus on their role as guardians of the secretory pathway.

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