Transient activation of the UPRER is an essential step in the acquisition of pluripotency during reprogramming

Somatic cells can be reprogrammed into pluripotent stem cells using the Yamanaka transcription factors. Reprogramming requires both epigenetic landscape reshaping and global remodeling of cell identity, structure, basic metabolic processes, and organelle form and function. We hypothesize that variable regulation of the proteostasis network and its influence upon the protein-folding environment within cells and their organelles is responsible for the low efficiency and stochasticity of reprogramming. We find that the unfolded protein response of the endoplasmic reticulum (UPRER), the mitochondrial UPR, and the heat shock response, which ensure proteome quality during stress, are activated during reprogramming. The UPRER is particularly crucial, and its ectopic, transient activation, genetically or pharmacologically, enhances reprogramming. Last, stochastic activation of the UPRER predicts reprogramming efficiency in naïve cells. Thus, the low efficiency and stochasticity of cellular reprogramming are due partly to the inability to properly initiate the UPRER to remodel the ER and its proteome.

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Transient activation of the UPRER is an essential step in the acquisition of pluripotency during reprogramming

10.1101/472787 ◽

2018 ◽

Author(s):

Milos S. Simic ◽

Erica Moehle ◽

Robert T. Schinzel ◽

Franziska Lorbeer ◽

Damien Jullié ◽

...

Keyword(s):

Unfolded Protein Response ◽

Cellular Reprogramming ◽

Pluripotent State ◽

Form And Function ◽

Unfolded Protein ◽

Er Stress Response ◽

Transient Activation ◽

Low Efficiency ◽

And Function ◽

Protein Response

AbstractSomatic cells can be reprogrammed into pluripotent stem cells by the forced expression of the OCT4, SOX2, KLF4 and c-MYC transcription factors. This process requires the reshaping of not only epigenetic landscapes, but the global remodeling of cell identity, structure, and function including such basic processes of metabolism and organelle form and function. Cellular reprogramming is a stochastic process with only a marginally measureable fraction of cells successfully crossing these, and many other, cellular epitomes to acquire the fully pluripotent state. We hypothesize that this variation is due, in part, by variable regulation of the proteostasis network and its influence upon the protein folding environment within cells and their organelles upon the remodeling process. We find that the endoplasmic reticulum unfolded protein response (UPRER), the heat-shock response (HSR) and the mitochondrial unfolded protein response (UPRmt), which monitor and ensure the quality of the proteome of, respectively, the ER, the cytosol and the mitochondria during stress, are activated during cellular reprogramming. Particularly, we find that the UPRER is essential for reprograming, and ectopic, transient activation of the UPRER, either genetically or pharmacologically, enhances the success of cells to reach a pluripotent state. Finally, and most revealing, we find that stochastic activation of the UPRER can predict the reprogramming efficiency of naïve cells. The results of these experiments indicate that the low efficiency and stochasticity of cellular reprogramming is partly the result of the inability to initiate a proper ER stress response for remodeling of the ER and its proteome during the reprogramming process. The results reported here display only one aspect of the proteostasis network and suggest that proper regulation of many more components of this network might be essential to acquire the pluripotent state.

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Stressed: The Unfolded Protein Response in T Cell Development, Activation, and Function

International Journal of Molecular Sciences ◽

10.3390/ijms20071792 ◽

2019 ◽

Vol 20 (7) ◽

pp. 1792 ◽

Cited By ~ 4

Author(s):

Kyeorda Kemp ◽

Cody Poe

Keyword(s):

Endoplasmic Reticulum ◽

T Cell ◽

Unfolded Protein Response ◽

T Cell Development ◽

Cell Development ◽

Secretory Cells ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

And Function ◽

Protein Response

The unfolded protein response (UPR) is a highly conserved pathway that allows cells to respond to stress in the endoplasmic reticulum caused by an accumulation of misfolded and unfolded protein. This is of great importance to secretory cells because, in order for proteins to traffic from the endoplasmic reticulum (ER), they need to be folded appropriately. While a wealth of literature has implicated UPR in immune responses, less attention has been given to the role of UPR in T cell development and function. This review discusses the importance of UPR in T cell development, homeostasis, activation, and effector functions. We also speculate about how UPR may be manipulated in T cells to ameliorate pathologies.

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Chemotherapy: induction of stress responses

Endocrine Related Cancer ◽

10.1677/erc.1.01272 ◽

2006 ◽

Vol 13 (Supplement_1) ◽

pp. S115-S124 ◽

Cited By ~ 57

Author(s):

E Tiligada

Keyword(s):

Anticancer Agents ◽

Stress Responses ◽

Chemotherapeutic Agents ◽

Clinical Value ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Shock Proteins ◽

And Function ◽

Protein Response ◽

Functional Components

Eukaryotic cells, from yeast to mammals, respond and adapt to environmental and microenvironmental stressors by evolutionary conserved multicomponent endogenous systems that utilise a network of signal transduction pathways to regulate the adaptive and protective phenotype. The balance between cell survival and cell death is decisive for sensitivity or resistance to DNA-damaging chemotherapeutic agents. Anticancer drugs may themselves act as stressors to induce adaptive signals that could limit their clinical value. Related research has been focused on the modulation of the expression and function of the heat shock proteins, the unfolded protein response, the mechanisms of subcellular translocation of signalling components, the genomic and non-genomic actions of drugs and endogenous functional components like hormonal pathways, the input of inflammation and alterations in the microenvironmental milieu and on the control of the cell cycle and proliferation. The outcome seems to be driven by the first-line responses that support cellular integrity and by specific mechanisms that depend on the type of cell and the nature, and duration and severity of the noxious stimulus. Data obtained from experimental organisms like the yeast have added valuable information on the basic conservation in cellular stress-related processes in eukaryotes and on the consequences that may accompany the adaptive and protective phenotype during the stress response to anticancer agents. Understanding the complex molecular pathways mediating these processes has started to contribute to the reevaluation of the current therapeutic regiments and to revolutionise the approaches for improved anticancer therapy.

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The Impact of Endoplasmic Reticulum-Associated Protein Modifications, Folding and Degradation on Lung Structure and Function

Frontiers in Physiology ◽

10.3389/fphys.2021.665622 ◽

2021 ◽

Vol 12 ◽

Author(s):

Emily M. Nakada ◽

Rui Sun ◽

Utako Fujii ◽

James G. Martin

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Unfolded Protein ◽

Lung Structure ◽

Selective Translation ◽

The Unfolded Protein Response ◽

And Function ◽

Protein Response ◽

Er Homeostasis ◽

The Impact

The accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) causes ER stress and induces the unfolded protein response (UPR) and other mechanisms to restore ER homeostasis, including translational shutdown, increased targeting of mRNAs for degradation by the IRE1-dependent decay pathway, selective translation of proteins that contribute to the protein folding capacity of the ER, and activation of the ER-associated degradation machinery. When ER stress is excessive or prolonged and these mechanisms fail to restore proteostasis, the UPR triggers the cell to undergo apoptosis. This review also examines the overlooked role of post-translational modifications and their roles in protein processing and effects on ER stress and the UPR. Finally, these effects are examined in the context of lung structure, function, and disease.

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Mitochondrial translation and dynamics synergistically extend lifespan in C. elegans through HLH-30

10.1101/871079 ◽

2019 ◽

Author(s):

Yasmine J. Liu ◽

Rebecca L. McIntyre ◽

Georges E. Janssens ◽

Evan G. Williams ◽

Jiayi Lan ◽

...

Keyword(s):

Synergistic Effect ◽

Mitochondrial Network ◽

Mitochondrial Translation ◽

C Elegans ◽

Form And Function ◽

Unfolded Protein ◽

Lysosome Biogenesis ◽

And Function ◽

Protein Response ◽

Mitochondrial Unfolded Protein Response

AbstractMitochondrial form and function, such as translation, are closely interlinked in homeostasis and aging. Inhibiting mitochondrial translation is known to increase lifespan in C. elegans, which is accompanied by a fragmented mitochondrial network. However, the causality between mitochondrial translation and morphology in longevity remains uncharacterized. Here, we show in C. elegans that disrupting mitochondrial network homeostasis by either blocking fission or fusion synergizes with the reduced mitochondrial translation to substantially prolong lifespan and stimulate stress response such as the mitochondrial unfolded protein response, UPRMT. Conversely, immobilizing the mitochondrial network through a simultaneous abrogation of fission and fusion reverses the lifespan increase induced by mitochondrial translation inhibition. Furthermore, we find that the synergistic effect of inhibiting both mitochondrial translation and dynamics on lifespan, despite stimulating UPRMT, does not require it. Instead, this lifespan-extending synergy is exclusively dependent on the lysosome biogenesis and autophagy transcription factor HLH-30/TFEB. Altogether, our study reveals the mechanistic connections between mitochondrial translation and dynamics in regulating longevity.SUMMARYMitochondrial form and function are intimately intertwined. Liu et al. find the synergistic effect of inhibiting both mitochondrial translation and dynamics on lifespan. This synergy is dependent on the induction of lysosome biogenesis through the nuclear localization of HLH-30.

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Role of unfolded protein response in genital malformation/damage of male mice induced by flutamide

Human & Experimental Toxicology ◽

10.1177/0960327120937049 ◽

2020 ◽

Vol 39 (12) ◽

pp. 1690-1699

Author(s):

H Yu ◽

K Wen ◽

X Zhou ◽

Y Zhang ◽

Z Yan ◽

...

Keyword(s):

Unfolded Protein Response ◽

Messenger Rna ◽

Hypoxia Inducible Factor ◽

Reproductive Organs ◽

Pregnant Mouse ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

And Function ◽

Protein Response

The unfolded protein response (UPR) is one of a switch of autophagy and apoptosis, and the endoplasmic reticulum stress (ERS) which inducing UPR plays a role in the malformations caused by some genetic and environmental factors. Exposure to flutamide during pregnancy will also cause abnormalities in some male offspring reproductive organs such as cryptorchidism. In this study, after administered the pregnant mouse orally at a dose of 300 mg/kg body weight every day during gestational day (GD)12 to GD18, flutamide can not only caused hypospadias in the male mouse offspring but also damaged the morphology and function of their testis. And the expression of UPR-related genes and proteins, autophagy, apoptosis, and angiogenesis-related genes of the damaged/teratogenic testis and penis in the mice were investigated to determine the role of UPR in this model. It was found that flutamide activated maybe the Atg7-Atg3-Lc3 pathway through the UPR pathway, caused cells excessive autophagy and apoptosis, and inhibited the formation of penile and testicular blood vessels by activating UPR and affecting the messenger RNA level of vascular endothelial growth factor and hypoxia-inducible factor 1.

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Mitochondrial translation and dynamics synergistically extend lifespan in C. elegans through HLH-30

The Journal of Cell Biology ◽

10.1083/jcb.201907067 ◽

2020 ◽

Vol 219 (6) ◽

Cited By ~ 4

Author(s):

Yasmine J. Liu ◽

Rebecca L. McIntyre ◽

Georges E. Janssens ◽

Evan G. Williams ◽

Jiayi Lan ◽

...

Keyword(s):

Mitochondrial Dynamics ◽

Mitochondrial Network ◽

Mitochondrial Translation ◽

C Elegans ◽

Form And Function ◽

Unfolded Protein ◽

Lysosome Biogenesis ◽

And Function ◽

Protein Response ◽

Mitochondrial Unfolded Protein Response

Mitochondrial form and function are closely interlinked in homeostasis and aging. Inhibiting mitochondrial translation is known to increase lifespan in C. elegans, and is accompanied by a fragmented mitochondrial network. However, whether this link between mitochondrial translation and morphology is causal in longevity remains uncharacterized. Here, we show in C. elegans that disrupting mitochondrial network homeostasis by blocking fission or fusion synergizes with reduced mitochondrial translation to prolong lifespan and stimulate stress response such as the mitochondrial unfolded protein response, UPRMT. Conversely, immobilizing the mitochondrial network through a simultaneous disruption of fission and fusion abrogates the lifespan increase induced by mitochondrial translation inhibition. Furthermore, we find that the synergistic effect of inhibiting both mitochondrial translation and dynamics on lifespan, despite stimulating UPRMT, does not require it. Instead, this lifespan-extending synergy is exclusively dependent on the lysosome biogenesis and autophagy transcription factor HLH-30/TFEB. Altogether, our study reveals the mechanistic crosstalk between mitochondrial translation, mitochondrial dynamics, and lysosomal signaling in regulating longevity.

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ER-mitochondria contact sites in neurodegeneration: genetic screening approaches to investigate novel disease mechanisms

Cell Death and Differentiation ◽

10.1038/s41418-020-00705-8 ◽

2020 ◽

Author(s):

Emma Louise Wilson ◽

Emmanouil Metzakopian

Keyword(s):

Neurodegenerative Diseases ◽

High Throughput Screening ◽

Current Knowledge ◽

Unfolded Protein ◽

Advantages And Disadvantages ◽

Contact Sites ◽

The Unfolded Protein Response ◽

And Function ◽

Protein Response ◽

Related Proteins

AbstractMitochondria-ER contact sites (MERCS) are known to underpin many important cellular homoeostatic functions, including mitochondrial quality control, lipid metabolism, calcium homoeostasis, the unfolded protein response and ER stress. These functions are known to be dysregulated in neurodegenerative diseases, including Parkinson’s disease (PD), Alzheimer’s disease (AD) and amyloid lateral sclerosis (ALS), and the number of disease-related proteins and genes being associated with MERCS is increasing. However, many details regarding MERCS and their role in neurodegenerative diseases remain unknown. In this review, we aim to summarise the current knowledge regarding the structure and function of MERCS, and to update the field on current research in PD, AD and ALS. Furthermore, we will evaluate high-throughput screening techniques, including RNAi vs CRISPR/Cas9, pooled vs arrayed formats and how these could be combined with current techniques to visualise MERCS. We will consider the advantages and disadvantages of each technique and how it can be utilised to uncover novel protein pathways involved in MERCS dysfunction in neurodegenerative diseases.

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ER homeostasis and autophagy

Essays in Biochemistry ◽

10.1042/ebc20170092 ◽

2017 ◽

Vol 61 (6) ◽

pp. 625-635 ◽

Cited By ~ 69

Author(s):

Matthew Smith ◽

Simon Wilkinson

Keyword(s):

Secretory Proteins ◽

Unfolded Protein ◽

Effector Pathway ◽

Autophagy Pathway ◽

The Unfolded Protein Response ◽

And Function ◽

Protein Response ◽

Er Homeostasis ◽

Effector Mechanisms

The endoplasmic reticulum (ER) is a key site for lipid biosynthesis and folding of nascent transmembrane and secretory proteins. These processes are maintained by careful homeostatic control of the environment within the ER lumen. Signalling sensors within the ER detect perturbations within the lumen (ER stress) and employ downstream signalling cascades that engage effector mechanisms to restore homeostasis. The most studied signalling mechanism that the ER employs is the unfolded protein response (UPR), which is known to increase a number of effector mechanisms, including autophagy. In this chapter, we will discuss the emerging role of autophagy as a UPR effector pathway. We will focus on the recently discovered selective autophagy pathway for ER, ER-phagy, with particular emphasis on the structure and function of known mammalian ER-phagy receptors, namely FAM134B, SEC62, RTN3 and CCPG1. Finally, we conclude with our view of where the future of this field can lead our understanding of the involvement of ER-phagy in ER homeostasis.

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