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 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 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 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 The Endoplasmic Reticulum Stress/Unfolded Protein Response and Their Contributions to Parkinson’s Disease Physiopathology

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2495
Author(s):  
Cristine Alves da Costa ◽  
Wejdane El Manaa ◽  
Eric Duplan ◽  
Frédéric Checler
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Endoplasmic Reticulum ◽  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
Age Related ◽  
The Unfolded Protein Response ◽  
Protein Response

Parkinson’s disease (PD) is a multifactorial age-related movement disorder in which defects of both mitochondria and the endoplasmic reticulum (ER) have been reported. The unfolded protein response (UPR) has emerged as a key cellular dysfunction associated with the etiology of the disease. The UPR involves a coordinated response initiated in the endoplasmic reticulum that grants the correct folding of proteins. This review gives insights on the ER and its functioning; the UPR signaling cascades; and the link between ER stress, UPR activation, and physiopathology of PD. Thus, post-mortem studies and data obtained by either in vitro and in vivo pharmacological approaches or by genetic modulation of PD causative genes are described. Further, we discuss the relevance and impact of the UPR to sporadic and genetic PD pathology.

scholarly journals Adenoviral CCN gene transfers induce in vitro and in vivo endoplasmic reticulum stress and unfolded protein response

2016 ◽  
Vol 1863 (11) ◽  
pp. 2604-2612 ◽  
Author(s):  
Erawan Borkham-Kamphorst ◽  
Bettina Therese Steffen ◽  
Eddy Van de Leur ◽  
Lidia Tihaa ◽  
Ute Haas ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
Protein Response

scholarly journals The unfolded protein response and endoplasmic reticulum protein targeting machineries converge on the stress sensor IRE1

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Diego Acosta-Alvear ◽  
G Elif Karagöz ◽  
Florian Fröhlich ◽  
Han Li ◽  
Tobias C Walther ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Unfolded Protein Response ◽  
Protein Targeting ◽  
Protein Translocation ◽  
Unfolded Protein ◽  
Exit Tunnel ◽  
The Unfolded Protein Response ◽  
Protein Response

The protein folding capacity of the endoplasmic reticulum (ER) is tightly regulated by a network of signaling pathways, known as the unfolded protein response (UPR). UPR sensors monitor the ER folding status to adjust ER folding capacity according to need. To understand how the UPR sensor IRE1 maintains ER homeostasis, we identified zero-length crosslinks of RNA to IRE1 with single nucleotide precision in vivo. We found that IRE1 specifically crosslinks to a subset of ER-targeted mRNAs, SRP RNA, ribosomal and transfer RNAs. Crosslink sites cluster in a discrete region of the ribosome surface spanning from the A-site to the polypeptide exit tunnel. Moreover, IRE1 binds to purified 80S ribosomes with high affinity, indicating association with ER-bound ribosomes. Our results suggest that the ER protein translocation and targeting machineries work together with the UPR to tune the ER’s protein folding load.

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