scholarly journals Unfolded Protein Response of the Endoplasmic Reticulum in Tumor Progression and Immunogenicity

2017 ◽  
Vol 2017 ◽  
pp. 1-18 ◽  
Author(s):  
Yoon Seon Yoo ◽  
Hye Gyeong Han ◽  
Young Joo Jeon
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Tumor Progression ◽  
Unfolded Protein Response ◽  
Therapeutic Intervention ◽  
Transmembrane Proteins ◽  
Eukaryotic Cells ◽  
Protein Homeostasis ◽  
Unfolded Protein ◽  
Protein Response

The endoplasmic reticulum (ER) is a pivotal regulator of folding, quality control, trafficking, and targeting of secreted and transmembrane proteins, and accordingly, eukaryotic cells have evolved specialized machinery to ensure that the ER enables these proteins to acquire adequate folding and maturation in the presence of intrinsic and extrinsic insults. This adaptive capacity of the ER to intrinsic and extrinsic perturbations is important for maintaining protein homeostasis, which is termed proteostasis. Failure in adaptation to these perturbations leads to accumulation of misfolded or unassembled proteins in the ER, which is termed ER stress, resulting in the activation of unfolded protein response (UPR) of the ER and the execution of ER-associated degradation (ERAD) to restore homeostasis. Furthermore, both of the two axes play key roles in the control of tumor progression, inflammation, immunity, and aging. Therefore, understanding UPR of the ER and subsequent ERAD will provide new insights into the pathogenesis of many human diseases and contribute to therapeutic intervention in these diseases.

scholarly journals Activation of Mammalian Unfolded Protein Response Is Compatible with the Quality Control System Operating in the Endoplasmic Reticulum

2004 ◽  
Vol 15 (6) ◽  
pp. 2537-2548 ◽  
Author(s):  
Satomi Nadanaka ◽  
Hiderou Yoshida ◽  
Fumi Kano ◽  
Masayuki Murata ◽  
Kazutoshi Mori
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Control System ◽  
Golgi Apparatus ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Secretory Pathway ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
Protein Response

Newly synthesized secretory and transmembrane proteins are folded and assembled in the endoplasmic reticulum (ER) where an efficient quality control system operates so that only correctly folded molecules are allowed to move along the secretory pathway. The productive folding process in the ER has been thought to be supported by the unfolded protein response (UPR), which is activated by the accumulation of unfolded proteins in the ER. However, a dilemma has emerged; activation of ATF6, a key regulator of mammalian UPR, requires intracellular transport from the ER to the Golgi apparatus. This suggests that unfolded proteins might be leaked from the ER together with ATF6 in response to ER stress, exhibiting proteotoxicity in the secretory pathway. We show here that ATF6 and correctly folded proteins are transported to the Golgi apparatus via the same route and by the same mechanism under conditions of ER stress, whereas unfolded proteins are retained in the ER. Thus, activation of the UPR is compatible with the quality control in the ER and the ER possesses a remarkable ability to select proteins to be transported in mammalian cells in marked contrast to yeast cells, which actively utilize intracellular traffic to deal with unfolded proteins accumulated in the ER.

scholarly journals Constitutive XBP-1s-mediated activation of the endoplasmic reticulum unfolded protein response protects against pathological tau

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Sarah M. Waldherr ◽  
Timothy J. Strovas ◽  
Taylor A. Vadset ◽  
Nicole F. Liachko ◽  
Brian C. Kraemer
Keyword(s):  
Endoplasmic Reticulum ◽  
Unfolded Protein Response ◽  
Protein Homeostasis ◽  
Loss Of Function ◽  
Normal Functioning ◽  
Subcellular Compartment ◽  
Unfolded Protein ◽  
Multiple Strategies ◽  
Disease Mechanisms ◽  
Protein Response

Abstract To endure over the organismal lifespan, neurons utilize multiple strategies to achieve protein homeostasis (proteostasis). Some homeostatic mechanisms act in a subcellular compartment-specific manner, but others exhibit trans-compartmental mechanisms of proteostasis. To identify pathways protecting neurons from pathological tau protein, we employed a transgenic Caenorhabditis elegans model of human tauopathy exhibiting proteostatic disruption. We show normal functioning of the endoplasmic reticulum unfolded protein response (UPRER) promotes clearance of pathological tau, and loss of the three UPRER branches differentially affects tauopathy phenotypes. Loss of function of xbp-1 and atf-6 genes, the two main UPRER transcription factors, exacerbates tau toxicity. Furthermore, constitutive activation of master transcription factor XBP-1 ameliorates tauopathy phenotypes. However, both ATF6 and PERK branches of the UPRER participate in amelioration of tauopathy by constitutively active XBP-1, possibly through endoplasmic reticulum-associated protein degradation (ERAD). Understanding how the UPRER modulates pathological tau accumulation will inform neurodegenerative disease mechanisms.

scholarly journals The unfolded protein response of the endoplasmic reticulum supports mitochondrial biogenesis by buffering non-imported proteins

2021 ◽  
Author(s):  
Katharina Knoeringer ◽  
Carina Groh ◽  
Lena Kraemer ◽  
Kevin C Stein ◽  
Katja G Hansen ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Membrane Proteins ◽  
Unfolded Protein Response ◽  
Mitochondrial Membrane ◽  
Cellular Protein ◽  
Mitochondrial Proteins ◽  
Protein Homeostasis ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Almost all mitochondrial proteins are synthesized in the cytosol and subsequently targeted to mitochondria. The accumulation of non-imported precursor proteins occurring upon mitochondrial dysfunction can challenge cellular protein homeostasis. Here we show that blocking protein translocation into mitochondria results in the accumulation of mitochondrial membrane proteins at the endoplasmic reticulum, thereby triggering the unfolded protein response (UPR-ER). Moreover, we find that mitochondrial membrane proteins are also routed to the ER under physiological conditions. The levels of ER-resident mitochondrial precursors is enhanced by import defects as well as metabolic stimuli that increase the expression of mitochondrial proteins. Under such conditions, the UPR-ER is crucial to maintain protein homeostasis and cellular fitness. We propose the ER serves as a physiological buffer zone for those mitochondrial precursors that cannot be immediately imported into mitochondria while engaging the UPRER to adjust the ER proteostasis capacity to the extent of precursor accumulation.

scholarly journals Bypass of glycan-dependent glycoprotein delivery to ERAD by up-regulated EDEM1

2011 ◽  
Vol 22 (21) ◽  
pp. 3945-3954 ◽  
Author(s):  
Efrat Ron ◽  
Marina Shenkman ◽  
Bella Groisman ◽  
Yana Izenshtein ◽  
Julia Leitman ◽  
...  
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Unfolded Protein Response ◽  
Deletion Mutant ◽  
Carbohydrate Recognition Domain ◽  
Stringent Requirement ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Control Compartment

Trimming of mannose residues from the N-linked oligosaccharide precursor is a stringent requirement for glycoprotein endoplasmic reticulum (ER)-associated degradation (ERAD). In this paper, we show that, surprisingly, overexpression of ER degradation–enhancing α-mannosidase-like protein 1 (EDEM1) or its up-regulation by IRE1, as occurs in the unfolded protein response, overrides this requirement and renders unnecessary the expression of ER mannosidase I. An EDEM1 deletion mutant lacking most of the carbohydrate-recognition domain also accelerated ERAD, delivering the substrate to XTP3-B and OS9. EDEM1 overexpression also accelerated the degradation of a mutant nonglycosylated substrate. Upon proteasomal inhibition, EDEM1 concentrated together with the ERAD substrate in the pericentriolar ER-derived quality control compartment (ERQC), where ER mannosidase I and ERAD machinery components are localized, including, as we show here, OS9. We suggest that a nascent glycoprotein can normally dissociate from EDEM1 and be rescued from ERAD by reentering calnexin-refolding cycles, a condition terminated by mannose trimming. At high EDEM1 levels, glycoprotein release is prevented and glycan interactions are no longer required, canceling the otherwise mandatory ERAD timing by mannose trimming and accelerating the targeting to degradation.

scholarly journals Activation of the endoplasmic reticulum unfolded protein response reverses an inflammation-like response to cytoplasmic DNA

2018 ◽  
Author(s):  
Ashley B. Williams ◽  
Felix Heider ◽  
Jan-Erik Messling ◽  
Wilhelm Bloch ◽  
Björn Schumacher
Keyword(s):  
Endoplasmic Reticulum ◽  
Unfolded Protein Response ◽  
Inflammatory Responses ◽  
Protein Homeostasis ◽  
Dnase Ii ◽  
Unfolded Protein ◽  
Tissue Degeneration ◽  
Cytoplasmic Dna ◽  
Protein Response

SUMMARYInnate immune responses protect organisms against various insults, but may lead to tissue damage when aberrantly activated. In higher organisms, cytoplasmic DNA can trigger inflammation that can lead to tissue degeneration. Simpler in vivo models could shed new mechanistic light on how inflammatory responses to cytoplasmic DNA lead to pathology. Here we show that in DNase II-deficient Caenorhabditis elegans, persistent foreign cytoplasmic DNA leads to systemic tissue degeneration, and we identify impaired protein homeostasis as an inflammatory pathomechanism. This pathological outcome can be alleviated by improving protein homeostasis, either via ectopic induction of the endoplasmic reticulum unfolded protein response (UPRER) or by treatment with N-acetylglucosamine. Our results establish C. elegans as an ancestral metazoan model for studying outcomes of inflammation-like conditions caused by persistent cytoplasmic DNA and provide insight into potential therapies for conditions involving chronic inflammation.

scholarly journals Human tauopathies are not associated with an activated unfolded protein response

2019 ◽  
Author(s):  
A. P. Pitera ◽  
I. J. Hartnell ◽  
D. Boche ◽  
V. O’Connor ◽  
K. Deinhardt
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Progressive Supranuclear Palsy ◽  
Unfolded Protein Response ◽  
Tau Protein ◽  
Human Tissue ◽  
Protein Quality ◽  
Protein Tau ◽  
Unfolded Protein ◽  
Protein Response

AbstractTauopathies are the neurodegenerative diseases associated with the accumulation of misfolded tau protein. Despite many years of investigation, the mechanisms underpinning tau dependent proteinopathy remains to be elucidated. A protein quality control pathway within the endoplasmic reticulum (ER), called unfolded protein response (UPR), has been suggested as a possible response implicated in the misfolded tau-mediated neurodegeneration. However, the question arose: how does the cytosolic protein tau that does not enter the ER induce a response stemming from this compartment? In this study we investigated three different human tauopathies to establish whether these diseases are associated with the activation of UPR. We probed for the modulation of several reliable UPR markers in mRNA and proteins extracted from 20 brain samples from Alzheimer’s disease (AD) patients, 11 from Pick’s disease (PiD) and 10 from Progressive Supranuclear Palsy (PSP) patients coupled to equal numbers of age-matched non-demented controls. This showed that different markers of UPR are not changed in any of the human tauopathies investigated. Interestingly, UPR signatures were often observed in non-demented controls. These data from human tissue further support the emerging evidence that the accumulation of misfolded cytosolic tau does not drive a diseased associated activation of UPR.

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