scholarly journals Dysregulation of very-long-chain fatty acid metabolism causes membrane saturation and induction of the unfolded protein response

2020 ◽  
Vol 31 (1) ◽  
pp. 7-17 ◽  
Author(s):  
Yagmur Micoogullari ◽  
Sankha S. Basu ◽  
Jessie Ang ◽  
Nina Weisshaar ◽  
Nicholas D. Schmitt ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Acid Metabolism ◽  
Protein Quality ◽  
Lipid Homeostasis ◽  
Long Chain Fatty Acids ◽  
Long Chain Fatty Acid ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Long Chain

Increasing evidence suggests that lipid homeostasis is critical for protein quality control. Very-long-chain fatty acids (VLCFA) are rare and poorly understood species. Here, it is shown that dysregulation of VLCFA metabolism causes increased membrane saturation, endoplasmic reticulum stress, and unfolded protein response induction.

scholarly journals Ribosomal mistranslation leads to silencing of the unfolded protein response and increased mitochondrial biogenesis

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Dmitri Shcherbakov ◽  
Youjin Teo ◽  
Heithem Boukari ◽  
Adrian Cortes-Sanchon ◽  
Matilde Mantovani ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Mitochondrial Biogenesis ◽  
Protein Quality ◽  
Genetic Manipulation ◽  
Ubiquitin Proteasome System ◽  
Limiting Factor ◽  
Unfolded Protein ◽  
Comprehensive Picture ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract Translation fidelity is the limiting factor in the accuracy of gene expression. With an estimated frequency of 10−4, errors in mRNA decoding occur in a mostly stochastic manner. Little is known about the response of higher eukaryotes to chronic loss of ribosomal accuracy as per an increase in the random error rate of mRNA decoding. Here, we present a global and comprehensive picture of the cellular changes in response to translational accuracy in mammalian ribosomes impaired by genetic manipulation. In addition to affecting established protein quality control pathways, such as elevated transcript levels for cytosolic chaperones, activation of the ubiquitin-proteasome system, and translational slowdown, ribosomal mistranslation led to unexpected responses. In particular, we observed increased mitochondrial biogenesis associated with import of misfolded proteins into the mitochondria and silencing of the unfolded protein response in the endoplasmic reticulum.

scholarly journals Modulating protein quality control

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Lars Plate ◽  
Ryan J Paxman ◽  
R Luke Wiseman ◽  
Jeffery W Kelly
Keyword(s):  
Quality Control ◽  
Small Molecules ◽  
Unfolded Protein Response ◽  
Protein Misfolding ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Misfolding Diseases ◽  
Protein Response

Small molecules that modulate the unfolded protein response have the potential to treat a variety of human protein misfolding diseases.

scholarly journals Disruption of ceramide synthesis by CerS2 down-regulation leads to autophagy and the unfolded protein response

2009 ◽  
Vol 424 (2) ◽  
pp. 273-283 ◽  
Author(s):  
Stefka D. Spassieva ◽  
Thomas D. Mullen ◽  
Danyelle M. Townsend ◽  
Lina M. Obeid
Keyword(s):  
Unfolded Protein Response ◽  
Stress Responses ◽  
Apoptotic Cell ◽  
Sphingolipid Metabolism ◽  
Ceramide Synthase ◽  
Down Regulation ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Long Chain

Ceramide metabolism has come under recent scrutiny because of its role in cellular stress responses. CerS2 (ceramide synthase 2) is one of the six mammalian isoforms of ceramide synthase and is responsible for the synthesis of VLC (very-long-chain) ceramides, e.g. C24, C24:1. To study the role of CerS2 in ceramide metabolism and cellular homoeostasis, we down-regulated CerS2 using siRNA (small interfering RNA) and examined several aspects of sphingolipid metabolism and cell stress responses. CerS2 down-regulation had a broad effect on ceramide homoeostasis, not just on VLC ceramides. Surprisingly, CerS2 down-regulation resulted in significantly increased LC (long-chain) ceramides, e.g. C14, C16, and our results suggested that the increase was due to a ceramide synthase-independent mechanism. CerS2-down-regulation-induced LC ceramide accumulation resulted in growth arrest which was not accompanied by apoptotic cell death. Instead, cells remained viable, showing induction of autophagy and activation of PERK [PKR (double-stranded-RNA-dependent protein kinase)-like endoplasmic reticulum kinase] and IRE1 (inositol-requiring 1) pathways [the latter indicating activation of the UPR (unfolded protein response)].

scholarly journals First Insights on the Presence of the Unfolded Protein Response in Human Spermatozoa

2019 ◽  
Vol 20 (21) ◽  
pp. 5518 ◽  
Author(s):  
Santiago ◽  
Silva ◽  
Fardilha
Keyword(s):  
Unfolded Protein Response ◽  
Protein Quality ◽  
Male Gamete ◽  
Human Sperm ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Related Proteins ◽  
The Impact

The unfolded protein response (UPR) is involved in protein quality control and is activated in response to several stressors. Although in testis the UPR mechanisms are well described, their presence in spermatozoa is contentious. We aimed to investigate the presence of UPR-related proteins in human sperm and the impact of oxidative stress induction in UPR activation. To identify UPR-related proteins in human sperm, a bioinformatic approach was adopted. To explore the activation of UPR, sperm were exposed to hydrogen peroxide (H2O2) and motility, vitality, and the levels of UPR-related proteins were assessed. We identified 97 UPR-related proteins in human sperm and showed, for the first time, the presence of HSF1, GADD34, and phosphorylated eIF2α. Additionally, the exposure of human sperm to H2O2 resulted in a significant decrease in sperm viability and motility and an increase in the levels of HSF1, HSP90, HSP60, HSP27, and eIF2α; all proteins involved in sensing and response to unfolded proteins. This study gave us a first insight into the presence of UPR mechanisms in the male gamete. However, the belief that sperm are devoid of transcription and translation highlight the need to clarify if these pathways are activated in sperm in the same way as in somatic cells.

scholarly journals Molecular Investigation of the Unfolded Protein Response in Select Human Tauopathies

2021 ◽  
pp. 1-15
Author(s):  
Aleksandra P. Pitera ◽  
Iain J. Hartnell ◽  
Lucy Scullard ◽  
Kirsten L. Williamson ◽  
Delphine Boche ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Unfolded Protein Response ◽  
Late Stage ◽  
Protein Quality ◽  
Cellular Responses ◽  
Cortical Tissue ◽  
Unfolded Protein ◽  
Molecular Investigation ◽  
The Unfolded Protein Response ◽  
Protein Response

Background: Tauopathies are a group of neurodegenerative diseases associated with the accumulation of misfolded tau protein. The mechanisms underpinning tau-dependent proteinopathy remain to be elucidated. A protein quality control pathway within the endoplasmic reticulum, the unfolded protein response (UPR), has been suggested as a possible pathway modulating cellular responses in a range of neurodegenerative diseases, including those associated with misfolded cytosolic tau. Objective: In this study we investigated three different clinically defined tauopathies to establish whether these diseases are accompanied by the activation of UPR. Methods: We used PCR and western blotting to probe for the modulation of several reliable UPR markers in mRNA and proteins extracted from three distinct tauopathies: 20 brain samples from Alzheimer’s disease patients, 11 from Pick’s disease, and 10 from progressive supranuclear palsy. In each disease samples from these patients were compared with equal numbers of age-matched non-demented controls. Results: Our investigation showed that different markers of UPR are not changed at the late stage of any of the human tauopathies investigated. Interestingly, UPR signatures were often observed in non-demented controls. Conclusion: These data from late-stage human cortical tissue report an activation of UPR markers within the aged brain across all cohorts investigated and further support the emerging evidence that the accumulation of misfolded cytosolic tau does not drive a diseased-associated activation of UPR.

Oestrogen-driven changes in the bovine uterus are associated with activation of the unfolded protein response

2014 ◽  
Author(s):  
Mohammed A Alfattah ◽  
Paul Anthony McGettigan ◽  
John Arthur Browne ◽  
Khalid M Alkhodair ◽  
Katarzyna Pluta ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response
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