Understanding Thyroid Cell Stress

Abstract Understanding the regulatory mechanisms that control intracellular stress has fundamental importance since its failure results in cell death. Evidence has emerged indicating that the intracellular signals that are induced in response to diverse stresses include the deoxyribonucleic acid damage response, the unfolded protein response, the mitochondrial and/or endoplasmic reticulum stress responses, and the autophagy signals to degrade dangerous protein aggregates. These signals bring changes to the stressed cells that may support systemic homeostasis or contribute to disease pathology. In normal thyroid cells, both reactive oxygen species (ROS) and antioxidant (AOD) activity is low. An increase in ROS balanced by AOD leads only to mild inflammation, but unopposed increases in ROS lead to a strong inflammatory response and may result in apoptosis. A balance between ROS and AOD is, therefore, needed to maintain thyrocyte homeostasis. This perspective describes how thyroid cells are subjected to multiple insults and how they try to protect themselves using these different cellular responses.

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Herpesviruses and the Unfolded Protein Response

Viruses ◽

10.3390/v12010017 ◽

2019 ◽

Vol 12 (1) ◽

pp. 17 ◽

Cited By ~ 9

Author(s):

Benjamin P. Johnston ◽

Craig McCormick

Keyword(s):

Unfolded Protein Response ◽

Stress Responses ◽

Immune Surveillance ◽

Lytic Replication ◽

Glycoprotein Synthesis ◽

Unfolded Protein ◽

Transcriptional Reprogramming ◽

Molecular Events ◽

The Unfolded Protein Response ◽

Protein Response

Herpesviruses usurp cellular stress responses to promote viral replication and avoid immune surveillance. The unfolded protein response (UPR) is a conserved stress response that is activated when the protein load in the ER exceeds folding capacity and misfolded proteins accumulate. The UPR aims to restore protein homeostasis through translational and transcriptional reprogramming; if homeostasis cannot be restored, the UPR switches from “helper” to “executioner”, triggering apoptosis. It is thought that the burst of herpesvirus glycoprotein synthesis during lytic replication causes ER stress, and that these viruses may have evolved mechanisms to manage UPR signaling to create an optimal niche for replication. The past decade has seen considerable progress in understanding how herpesviruses reprogram the UPR. Here we provide an overview of the molecular events of UPR activation, signaling and transcriptional outputs, and highlight key evidence that herpesviruses hijack the UPR to aid infection.

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Regulated Ire1-dependent mRNA decay requires no-go mRNA degradation to maintain endoplasmic reticulum homeostasis in S. pombe

eLife ◽

10.7554/elife.29216 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 34

Author(s):

Nicholas R Guydosh ◽

Philipp Kimmig ◽

Peter Walter ◽

Rachel Green

Keyword(s):

Endoplasmic Reticulum ◽

Critical Role ◽

Mrna Degradation ◽

Ribosome Profiling ◽

Unfolded Protein ◽

Selective Degradation ◽

Stressed Cells ◽

Novel Target ◽

The Unfolded Protein Response ◽

Protein Response

The unfolded protein response (UPR) monitors and adjusts the protein folding capacity of the endoplasmic reticulum (ER). In S. pombe, the ER membrane-resident kinase/endoribonuclease Ire1 utilizes a mechanism of selective degradation of ER-bound mRNAs (RIDD) to maintain homeostasis. We used a genetic screen to identify factors critical to the Ire1-mediated UPR and found several proteins, Dom34, Hbs1 and Ski complex subunits, previously implicated in ribosome rescue and mRNA no-go-decay (NGD). Ribosome profiling in ER-stressed cells lacking these factors revealed that Ire1-mediated cleavage of ER-associated mRNAs results in ribosome stalling and mRNA degradation. Stalled ribosomes iteratively served as a ruler to template precise, regularly spaced upstream mRNA cleavage events. This clear signature uncovered hundreds of novel target mRNAs. Our results reveal that the UPR in S. pombe executes RIDD in an intricate interplay between Ire1, translation, and the NGD pathway, and establish a critical role for NGD in maintaining ER homeostasis.

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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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ER stress and the unfolded protein response in intestinal inflammation

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00063.2010 ◽

2010 ◽

Vol 298 (6) ◽

pp. G820-G832 ◽

Cited By ~ 107

Author(s):

Michael A. McGuckin ◽

Rajaraman D. Eri ◽

Indrajit Das ◽

Rohan Lourie ◽

Timothy H. Florin

Keyword(s):

Er Stress ◽

Unfolded Protein Response ◽

Protein Misfolding ◽

Intestinal Inflammation ◽

Secretory Cells ◽

Unfolded Protein ◽

Bowel Diseases ◽

Stressed Cells ◽

The Unfolded Protein Response ◽

Protein Response

Endoplasmic reticulum (ER) stress is a phenomenon that occurs when excessive protein misfolding occurs during biosynthesis. ER stress triggers a series of signaling and transcriptional events known as the unfolded protein response (UPR). The UPR attempts to restore homeostasis in the ER but if unsuccessful can trigger apoptosis in the stressed cells and local inflammation. Intestinal secretory cells are susceptible to ER stress because they produce large amounts of complex proteins for secretion, most of which are involved in mucosal defense. This review focuses on ER stress in intestinal secretory cells and describes how increased protein misfolding could occur in these cells, the process of degradation of misfolded proteins, the major molecular elements of the UPR pathway, and links between the UPR and inflammation. Evidence is reviewed from mouse models and human inflammatory bowel diseases that ties ER stress and activation of the UPR with intestinal inflammation, and possible therapeutic approaches to ameliorate ER stress are discussed.

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GAS1Deficient Enhances UPR Activity inSaccharomyces cerevisiae

BioMed Research International ◽

10.1155/2019/1238581 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12

Author(s):

Hong-jing Cui ◽

Xin-gang Cui ◽

Xia Jing ◽

Yuan Yuan ◽

Ya-qin Chen ◽

...

Keyword(s):

Er Stress ◽

Stress Responses ◽

Molecular Mechanisms ◽

Yeast Cells ◽

Unfolded Protein ◽

Proliferation Ability ◽

The Unfolded Protein Response ◽

Protein Response ◽

Cycle Regulation ◽

Wild Type Yeast

Beta-1,3-glucanosyltransferase (Gas1p) plays important roles in cell wall biosynthesis and morphogenesis and has been implicated in DNA damage responses and cell cycle regulation in fungi. Yeast Gas1p has also been reported to participate in endoplasmic reticulum (ER) stress responses. However, the precise roles and molecular mechanisms through which Gas1p affects these responses have yet to be elucidated. In this study, we constructedGAS1-deficient (gas1Δ) andGAS1-overexpressing (GAS1 OE) yeast strains and observed that thegas1Δstrain exhibited a decreased proliferation ability and a shorter replicative lifespan (RLS), as well as enhanced activity of the unfolded protein response (UPR) in the absence of stress. However, under the high-tunicamycin-concentration (an ER stress-inducing agent; 1.0 μg/mL) stress, thegas1Δyeast cells exhibited an increased proliferation ability compared with the wild-type yeast strain. In addition, our findings demonstrated thatIRE1andHAC1(two upstream modulators of the UPR) are required for the survival ofgas1Δyeast cells under the tunicamycin stress. On the other hand, we provided evidence that theGAS1overexpression caused an obvious sensitivity to the low-tunicamycin-concentration (0.25 μg/mL). Collectively, our results indicate that Gas1p plays an important role in the ageing and ER stress responses in yeast.

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Multilevel regulation of endoplasmic reticulum stress responses in plants: where old roads and new paths meet

Journal of Experimental Botany ◽

10.1093/jxb/erz487 ◽

2019 ◽

Vol 71 (5) ◽

pp. 1659-1667 ◽

Cited By ~ 10

Author(s):

Taiaba Afrin ◽

Danish Diwan ◽

Katrina Sahawneh ◽

Karolina Pajerowska-Mukhtar

Keyword(s):

Endoplasmic Reticulum ◽

Stress Response ◽

Er Stress ◽

Stress Responses ◽

Translational Control ◽

Protein Quality ◽

Unfolded Protein ◽

Transcriptional Gene Regulation ◽

The Unfolded Protein Response ◽

Protein Response

Abstract The sessile lifestyle of plants requires them to cope with a multitude of stresses in situ. In response to diverse environmental and intracellular cues, plant cells respond by massive reprogramming of transcription and translation of stress response regulators, many of which rely on endoplasmic reticulum (ER) processing. This increased protein synthesis could exceed the capacity of precise protein quality control, leading to the accumulation of unfolded and/or misfolded proteins that triggers the unfolded protein response (UPR). Such cellular stress responses are multilayered and executed in different cellular compartments. Here, we will discuss the three main branches of UPR signaling in diverse eukaryotic systems, and describe various levels of ER stress response regulation that encompass transcriptional gene regulation by master transcription factors, post-transcriptional activities including cytoplasmic splicing, translational control, and multiple post-translational events such as peptide modifications and cleavage. In addition, we will discuss the roles of plant ER stress sensors in abiotic and biotic stress responses and speculate on the future prospects of engineering these signaling events for heightened stress tolerance.

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CPR5 modulates salicylic acid and the unfolded protein response to manage tradeoffs between plant growth and stress responses

The Plant Journal ◽

10.1111/tpj.13397 ◽

2017 ◽

Vol 89 (3) ◽

pp. 486-501 ◽

Cited By ~ 20

Author(s):

Zhe Meng ◽

Cristina Ruberti ◽

Zhizhong Gong ◽

Federica Brandizzi

Keyword(s):

Salicylic Acid ◽

Plant Growth ◽

Unfolded Protein Response ◽

Stress Responses ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

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Regulation of the unfolded protein response by noncoding RNA

AJP Cell Physiology ◽

10.1152/ajpcell.00293.2016 ◽

2017 ◽

Vol 313 (3) ◽

pp. C243-C254 ◽

Cited By ~ 21

Author(s):

Mari McMahon ◽

Afshin Samali ◽

Eric Chevet

Keyword(s):

Unfolded Protein Response ◽

Stress Responses ◽

Noncoding Rna ◽

Noncoding Rnas ◽

Small Noncoding Rna ◽

Downstream Signaling ◽

Unfolded Protein ◽

Cell Death Mechanisms ◽

The Unfolded Protein Response ◽

Protein Response

Cells are exposed to various intrinsic and extrinsic stresses in both physiological and pathological conditions. To adapt to those conditions, cells have evolved various mechanisms to cope with the disturbances in protein demand, largely through the unfolded protein response (UPR) in the endoplasmic reticulum (ER), but also through the integrated stress response (ISR). Both responses initiate downstream signaling to transcription factors that, in turn, trigger adaptive programs and/or in the case of prolonged stress, cell death mechanisms. Recently, noncoding RNAs, including microRNA and long noncoding RNA, have emerged as key players in the stress responses. These noncoding RNAs act as both regulators and effectors of the UPR and fine-tune the output of the stress signaling pathways. Although much is known about the UPR and the cross talk that exists between pathways, the contribution of small noncoding RNA has not been fully assessed. Herein we bring together and review the current known functions of noncoding RNA in regulating adaptive pathways in both physiological and pathophysiological conditions, illustrating how they operate within the known UPR functions and contribute to diverse cellular outcomes.

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The Unfolded Protein Response: An Overview

Biology ◽

10.3390/biology10050384 ◽

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.

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Salicylic acid-independent role of NPR1 is required for protection from proteotoxic stress in the plant endoplasmic reticulum

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1802254115 ◽

2018 ◽

Vol 115 (22) ◽

pp. E5203-E5212 ◽

Cited By ~ 19

Author(s):

Ya-Shiuan Lai ◽

Luciana Renna ◽

John Yarema ◽

Cristina Ruberti ◽

Sheng Yang He ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Salicylic Acid ◽

Er Stress ◽

Stress Responses ◽

Unfolded Protein ◽

Redox Activation ◽

Genetic Level ◽

The Unfolded Protein Response ◽

Protein Response

The unfolded protein response (UPR) is an ancient signaling pathway designed to protect cells from the accumulation of unfolded and misfolded proteins in the endoplasmic reticulum (ER). Because misregulation of the UPR is potentially lethal, a stringent surveillance signaling system must be in place to modulate the UPR. The major signaling arms of the plant UPR have been discovered and rely on the transcriptional activity of the transcription factors bZIP60 and bZIP28 and on the kinase and ribonuclease activity of IRE1, which splices mRNA to activate bZIP60. Both bZIP28 and bZIP60 modulate UPR gene expression to overcome ER stress. In this study, we demonstrate at a genetic level that the transcriptional role of bZIP28 and bZIP60 in ER-stress responses is antagonized by nonexpressor of PR1 genes 1 (NPR1), a critical redox-regulated master regulator of salicylic acid (SA)-dependent responses to pathogens, independently of its role in SA defense. We also establish that the function of NPR1 in the UPR is concomitant with ER stress-induced reduction of the cytosol and translocation of NPR1 to the nucleus where it interacts with bZIP28 and bZIP60. Our results support a cellular role for NPR1 as well as a model for plant UPR regulation whereby SA-independent ER stress-induced redox activation of NPR1 suppresses the transcriptional role of bZIP28 and bZIP60 in the UPR.

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