Faculty Opinions recommendation of Unfolded proteins are Ire1-activating ligands that directly induce the unfolded protein response.

2011 ◽  
Author(s):  
Martin Pool
Keyword(s):  
Unfolded Protein Response ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

scholarly journals Protein Serine/Threonine Phosphatase Ptc2p Negatively Regulates the Unfolded-Protein Response by Dephosphorylating Ire1p Kinase

1998 ◽  
Vol 18 (4) ◽  
pp. 1967-1977 ◽  
Author(s):  
Ajith A. Welihinda ◽  
Witoon Tirasophon ◽  
Sarah R. Green ◽  
Randal J. Kaufman
Keyword(s):  
Unfolded Protein Response ◽  
Transmembrane Protein ◽  
Null Alleles ◽  
Dependent Manner ◽  
Unfolded Proteins ◽  
Interaction Domain ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Upr Pathway

ABSTRACT Cells respond to the accumulation of unfolded proteins in the endoplasmic reticulum (ER) by increasing the transcription of the genes encoding ER-resident chaperone proteins. Ire1p is a transmembrane protein kinase that transmits the signal from unfolded proteins in the lumen of the ER by a mechanism that requires oligomerization andtrans-autophosphorylation of its cytoplasmic-nucleoplasmic kinase domain. Activation of Ire1p induces a novel spliced form ofHAC1 mRNA that produces Hac1p, a transcription factor that is required for activation of the transcription of genes under the control of the unfolded-protein response (UPR) element. Searching for proteins that interact with Ire1p in Saccharomyces cerevisiae, we isolated PTC2, which encodes a serine/threonine phosphatase of type 2C. The Ptc2p interaction with Ire1p is specific, direct, dependent on Ire1p phosphorylation, and mediated through a kinase interaction domain within Ptc2p. Ptc2p dephosphorylates Ire1p efficiently in an Mg2+-dependent manner in vitro. PTC2 is nonessential for growth and negatively regulates the UPR pathway. Strains carrying null alleles ofPTC2 have a three- to fourfold-increased UPR and increased levels of spliced HAC1 mRNA. Overexpression of wild-type Ptc2p but not catalytically inactive Ptc2p reduces levels of splicedHAC1 mRNA and attenuates the UPR, demonstrating that the phosphatase activity of Ptc2p is required for regulation of the UPR. These results demonstrate that Ptc2p downregulates the UPR by dephosphorylating Ire1p and reveal a novel mechanism of regulation in the UPR pathway upstream of the HAC1 mRNA splicing event.

scholarly journals The Unfolded Protein Response: An Overview

Biology ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 384
Author(s):  
Adam Read ◽  
Martin Schröder
Keyword(s):  
Gene Expression ◽  
Saccharomyces Cerevisiae ◽  
Unfolded Protein Response ◽  
Protein Homeostasis ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
Altered Glycosylation ◽  
Stressed Cells ◽  
The Unfolded Protein Response ◽  
Protein Response

The unfolded protein response is the mechanism by which cells control endoplasmic reticulum (ER) protein homeostasis. Under normal conditions, the UPR is not activated; however, under certain stresses, such as hypoxia or altered glycosylation, the UPR can be activated due to an accumulation of unfolded proteins. The activation of the UPR involves three signaling pathways, IRE1, PERK and ATF6, which all play vital roles in returning protein homeostasis to levels seen in non-stressed cells. IRE1 is the best studied of the three pathways, as it is the only pathway present in Saccharomyces cerevisiae. This pathway involves spliceosome independent splicing of HAC1 or XBP1 in yeast and mammalians cells, respectively. PERK limits protein synthesis, therefore reducing the number of new proteins requiring folding. ATF6 is translocated and proteolytically cleaved, releasing a NH2 domain fragment which is transported to the nucleus and which affects gene expression. If the UPR is unsuccessful at reducing the load of unfolded proteins in the ER and the UPR signals remain activated, this can lead to programmed cell death.

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.

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

2021 ◽  
Author(s):  
Toni Radanović ◽  
Robert Ernst
Keyword(s):  
Protein Folding ◽  
Unfolded Protein Response ◽  
Secretory Pathway ◽  
Membrane Lipids ◽  
Unfolded Proteins ◽  
Storage Lipids ◽  
Unfolded Protein ◽  
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 membrane insertion of proteins, 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 metabolism for membrane lipids 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.

scholarly journals Methods for Monitoring Endoplasmic Reticulum Stress and the Unfolded Protein Response

2010 ◽  
Vol 2010 ◽  
pp. 1-11 ◽  
Author(s):  
Afshin Samali ◽  
Una FitzGerald ◽  
Shane Deegan ◽  
Sanjeev Gupta
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Model Systems ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
Cellular Repair ◽  
Standard Set ◽  
The Unfolded Protein Response ◽  
Protein Response

The endoplasmic reticulum (ER) is the site of folding of membrane and secreted proteins in the cell. Physiological or pathological processes that disturb protein folding in the endoplasmic reticulum cause ER stress and activate a set of signaling pathways termed the Unfolded Protein Response (UPR). The UPR can promote cellular repair and sustained survival by reducing the load of unfolded proteins through upregulation of chaperones and global attenuation of protein synthesis. Research into ER stress and the UPR continues to grow at a rapid rate as many new investigators are entering the field. There are also many researchers not working directly on ER stress, but who wish to determine whether this response is activated in the system they are studying: thus, it is important to list a standard set of criteria for monitoring UPR in different model systems. Here, we discuss approaches that can be used by researchers to plan and interpret experiments aimed at evaluating whether the UPR and related processes are activated. We would like to emphasize that no individual assay is guaranteed to be the most appropriate one in every situation and strongly recommend the use of multiple assays to verify UPR activation.

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.

Endoplasmic reticulum stress and unfolded protein response in renal pathophysiology: Janus faces

2008 ◽  
Vol 295 (2) ◽  
pp. F323-F334 ◽  
Author(s):  
Masanori Kitamura
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Current Knowledge ◽  
Renal Diseases ◽  
Unfolded Proteins ◽  
Diverse Range ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

A number of pathophysiological insults lead to accumulation of unfolded proteins in the endoplasmic reticulum (ER) and cause ER stress. In response to accumulation of unfolded/misfolded proteins, cells adapt themselves to the stress condition via the unfolded protein response (UPR). For the cells, UPR is a double-edged sword. It triggers both prosurvival and proapoptotic signals. ER stress and UPR may, therefore, be involved in a diverse range of pathological situations. However, currently, information is limited regarding roles of ER stress and UPR in the renal pathophysiology. This review describes current knowledge on the relationship between ER stress and diseases and summarizes evidence for the link between ER stress/UPR and renal diseases.

scholarly journals How chloroplasts protect themselves from unfolded proteins

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Felix Kessler ◽  
Paolo Longoni
Keyword(s):  
Unfolded Protein Response ◽  
Genetic Screen ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

A genetic screen has identified the first signaling component of the unfolded protein response in chloroplasts.

scholarly journals Functional analysis of the mammalian RNA ligase for IRE1 in the unfolded protein response

2017 ◽  
Vol 37 (2) ◽  
Author(s):  
Juthakorn Poothong ◽  
Witoon Tirasophon ◽  
Randal J. Kaufman
Keyword(s):  
Escherichia Coli ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Mammalian Cells ◽  
Unfolded Proteins ◽  
Rna Ligase ◽  
Unfolded Protein ◽  
Rna Ligation ◽  
The Unfolded Protein Response ◽  
Protein Response

The unfolded protein response (UPR) is a conserved signalling pathway activated on the accumulation of unfolded proteins within the endoplasmic reticulum (ER), termed ER stress. Upon ER stress, HAC1/XBP1 undergoes exon/intron-specific excision by inositol requiring enzyme 1 (IRE1) to remove an intron and liberate the 5′ and 3′ exons. In yeast, the 5′ and 3′ HAC1 exons are subsequently ligated by tRNA ligase (Rlg1p), whereas XBP1 ligation in mammalian cells is catalysed by a recently identified ligase, RtcB. In the present study, RNA ligase activity of the human RtcB (hRtcB) involved in the unconventional splicing of XBP1/HAC1 mRNA was explored in an rlg1-100 mutant yeast strain. Distinct from Escherichia coli RtcB and Rlg1p, expression of hRtcB alone inefficiently complemented HAC1/XBP1 splicing and the hRtcB cofactor (archease) was required to promote enzymatic activity of hRtcB to catalyse RNA ligation.

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