The physiological role of the unfolded protein response in the nervous system

The unfolded protein response(UPR)is a cellular stress response pathway activated when the endoplasmic reticulum,a crucial organelle for protein folding and modification,encounters an accumulation of unfolded or misfolded proteins.The UPR aims to restore endoplasmic reticulum homeostasis by enhancing protein folding capacity,reducing protein biosynthesis,and promoting protein degradation.It also plays a pivotal role in coordinating signaling cascades to determine cell fate and function in response to endoplasmic reticulum stress.Recent research has highlighted the significance of the UPR not only in maintaining endoplasmic reticulum homeostasis but also in influencing various physiological processes in the nervous system.Here,we provide an overview of recent findings that underscore the UPR’s involvement in preserving the function and viability of neuronal and myelinating cells under physiological conditions,and highlight the critical role of the UPR in brain development,memory storage,retinal cone development,myelination,and maintenance of myelin thickness.

Mesenchymal stromal cells modulate unfolded protein response and preserve β-cell mass in type 1 diabetes

Introduction:Transplantation of mesenchymal stromal cells(MSCs)is a promising therapy for type 1 diabetes(T1D).However,whether the infused MSCs affect the endoplasmic reticulum stress or subsequent unfolded protein response inβcells remains unclear.Methods:To investigate this,we induced early-onset T1D in non-obese diabetic mice using streptozotocin.Subsequently,T1D mice were randomly assigned to receive either MSCs or phosphate-buffered saline.We observed the in vivo homing of MSCs and assessed their effectiveness by analyzing blood glucose levels,body weight,histopathology,pancreatic protein expression,and serum levels of cytokines,proinsulin,and C-peptide.Results:Infused MSCs were found in the lungs,liver,spleen,and pancreas of T1D mice.They exhibited various effects,including reducing blood glucose levels,regulating immunity,inhibiting inflammation,increasingβ-cell areas,and reducing the expression of key proteins in the unfolded protein response pathway.Fasting serum proinsulin and C-peptide levels were significantly higher in the MSCs treatment group than in the T1D model group.However,there was no significant difference in the biomarker ofβ-cell endoplasmic reticulum stress,the ratio of fasting serum proinsulin to C-peptide,between the two groups.Conclusion:Ourfindings reveal that MSCs infusion does not alleviate endoplasmic reticulum stress inβcells directly but modulates the unfolded protein response pathway to preserveβ-cell mass and function in T1D mice.

Hypoxia Affects Autophagy in Human Umbilical Vein Endothelial Cells via the IRE1 Unfolded Protein Response

Objective:The purpose of this study was to investigate the role of the unfolded protein response,specifically the inositol-requiring enzyme 1(IRE1)signaling pathway,in hypoxia-induced autophagy in human umbilical venous endothelial cells(HUVECs).Methods:The expression of IRE1 and autophagy relative protein in HUVECs with hypoxia was explored by Western blotting,qRT-PCR and confocal microscopy.Further,we evaluated the biological effects of HUVECs by tube formation assay and wound healing assay in vitro.Finally,we examined the function of IRE1 in local blood vessels through animal models,Results:Hypoxia activated the IRE1 signaling pathway and induced autophagy in a time-dependent manner in HUVECs and further influenced the biological effects of HUVECs.Intraperitoneal injection of IRE1 inhibitors inhibited local vascular autophagy levels and lipid accumulation in model animals.Conclusion:Hypoxia can induce autophagy and activate the IRE1 signaling pathway in HUVECs and the IRE1 signaling pathway is involved in autophagy in hypoxic conditions.

The Role and Mechanism of Unfolded Protein Response Pathway in Tumor Drug Resistance

In the process of tumor proliferation and metastasis,tumor cells encounter hypoxia,low glucose,acidosis,and other stressful environments.These conditions prompt tumor cells to generate endoplasmic reticulum stress(ERS).As a signal mechanism that mitigates ERS in eukaryotic cells,the unfolded protein response(UPR)pathway can activate cells and tissues,regulating pathological activities in various cells,and maintaining ER homeostasis.It forms the most crucial adaptive and defensive mechanism for cells.However,under the continuous influence of chemotherapy drugs,the quantity of unfolded proteins and erroneous proteins produced by tumor cells significantly increases,surpassing the normal regulatory range of UPR.Consequently,ERS fails to function properly,fostering tumor cell proliferation and the development of drug resistance.This review delves into the study of three UPR pathways(PERK,IRE1,and ATF6),elucidating the mechanisms of drug resistance and research progress in the signal transduction pathway of UPR related to cancers.It provides a profound understanding of the role and relationship between UPR and anti-tumor drugs,offering a new direction for effective clinical treatment.

Roles of mitochondrial unfolded protein response in mammalian stem cells

The mitochondrial unfolded protein response(UPRmt)is an evolutionarily conserved adaptive mechanism for improving cell survival under mitochondrial stress.Under physiological and pathological conditions,the UPRmt is the key to maintaining intracellular homeostasis and proteostasis.Important roles of the UPRmt have been demonstrated in a variety of cell types and in cell development,metabolism,and immune processes.UPRmt dysfunction leads to a variety of pathologies,including cancer,inflammation,neurodegenerative disease,metabolic disease,and immune disease.Stem cells have a special ability to selfrenew and differentiate into a variety of somatic cells and have been shown to exist in a variety of tissues.These cells are involved in development,tissue renewal,and some disease processes.Although the roles and regulatory mechanisms of the UPRmt in somatic cells have been widely reported,the roles of the UPRmt in stem cells are not fully understood.The roles and functions of the UPRmt depend on stem cell type.Therefore,this paper summarizes the potential significance of the UPRmt in embryonic stem cells,tissue stem cells,tumor stem cells,and induced pluripotent stem cells.The purpose of this review is to provide new insights into stem cell differentiation and tumor pathogenesis.

The unfolded protein response signaling and retinal Müller cell metabolism

The retina is one of the most energy demanding tissues in the body. Like most neurons in the central nervous system, retinal neurons consume high amounts of adenosine-5′-triphosphate（ATP） to generate visual signal and transmit the information to the brain. Disruptions in retinal metabolism can cause neuronal dysfunction and degeneration resulting in severe visual impairment and even blindness. The homeostasis of retinal metabolism is tightly controlled by multiple signaling pathways, such as the unfolded protein response（UPR）, and the close interactions between retinal neurons and other retinal cell types including vascular cells and Müller glia. The UPR is a highly conserved adaptive cellular response and can be triggered by many physiological stressors and pathophysiological conditions. Activation of the UPR leads to changes in glycolytic rate, ATP production, de novo serine synthesis, and the hexosamine biosynthetic pathway, which are considered critical components of Müller glia metabolism and provide metabolic support to surrounding neurons. When these pathways are disrupted, neurodegeneration occurs rapidly. In this review, we summarize recent advance in studies of the UPR in Müller glia and highlight the potential role of the UPR in retinal degeneration through regulation of Müller glia metabolism.

A vicinal oxygen chelate protein facilitates viral infection by triggering the unfolded protein response in Nicotiana benthamiana

Vicinal oxygen chelate(VOC)proteins are members of an enzyme superfamily with dioxygenase or non-dioxygenase activities.However,the biological functions of VOC proteins in plants are poorly understood.Here,we show that a VOC in Nicotiana benthamiana(NbVOC1)facilitates viral infection.NbVOC1 was significantly induced by infection by beet necrotic yellow vein virus(BNYVV).Transient overexpression of NbVOC1 or its homolog from Beta vulgaris(BvVOC1)enhanced BNYVV infection in N.benthamiana,which required the nuclear localization of VOC1.Consistent with this result,overexpressing NbVOC1 facilitated BNYVV infection,whereas,knockdown and knockout of NbVOC1 inhibited BNYVV infection in transgenic N.benthamiana plants.NbVOC1 interacts with the basic leucine zipper transcription factors bZIP17/28,which enhances their self-interaction and DNA binding to the promoters of unfolded protein response(UPR)-related genes.We propose that bZIP17/28 directly binds to the NbVOC1 promoter and induces its transcription,forming a positive feedback loop to induce the UPR and facilitating BNYVV infection.Collectively,our results demonstrate that NbVOC1 positively regulates the UPR that enhances viral infection in plants.

New insights into the unfolded protein response(UPR)-anterior gradient 2(AGR2)pathway in the regulation of intestinal barrier function in weaned piglets

Sustained dysfunction of the intestinal barrier caused by early weaning is a major factor that induces postweaning diarrhea in weaned piglets.In both healthy and diseased states,the intestinal barrier is regulated by goblet cells.Alterations in the characteristics of goblet cells are linked to intestinal barrier dysfunction and inflammatory conditions during pathogenic infections.In this review,we summarize the current understanding of the mechanisms of the unfolded protein response(UPR)and anterior gradient2(AGR2)in maintaining intestinal barrier function and how modifications to these systems affect mucus barrier characteristics and goblet cell dysregulation.We highlight a novel mechanism underlying the UPR-AGR2 pathway,which affects goblet cell differentiation and maturation and the synthesis and secretion of mucin by regulating epidermal growth factor receptor and mucin 2.This study provides a theoretical basis and new insights into the regulation of intestinal health in weaned piglets.

Molecular signal networks and regulating mechanisms of the unfolded protein response

Within the cell, several mechanisms exist to maintain homeostasis of the endoplasmic reticulum （ER）. One of the primary mechanisms is the unfolded protein response （UPR）. In this review, we primarily focus on the latest signal webs and regulation mechanisms of the UPR. The relationships among ER stress, apoptosis, and cancer are also discussed. Under the normal state, binding immunoglobulin protein （BiP） interacts with the three sensors （protein kinase RNA-like ER kinase （PERK）, activating transcription factor 6 （ATF6）, and inositol-requiring enzyme la （IREla）） Under ER stress, misfolded proteins interact with BiP, resulting in the release of BiP from the sensors. Subsequently, the three sensors dimerize and autophosphorylate to promote the signal cascades of ER stress. ER stress includes a series of positive and negative feedback signals, such as those regulating the stabilization of the sensors/BiP complex, activating and inactivating the sensors by autophosphorylation and dephosphorylation, activating specific transcription factors to enable selective transcription, and augmenting the ability to refold and export. Apart from the three basic pathways, vascular endothelial growth factor （VEGF）-VEGF receptor （VEGFR）-phospholipase C-~ （PLCy）-mammalian target of rapamycin complex 1 （mTORC1） pathway, induced only in solid tumors, can also activate ATF6 and PERK signal cascades, and IREla also can be activated by activated RAC-alpha serine/threonine-protein kinase （AKT）. A moderate UPR functions as a pro-survival signal to return the cell to its state of homeostasis. However, persistent ER stress will induce cells to undergo apoptosis in response to increasing reactive oxygen species （ROS）, Ca2＋ in the cytoplasmic matrix, and other apoptosis signal cascades, such as c-Jun N-terminal kinase （JNK）, signal transducer and activator of transcription 3 （STAT3）, and P38, when cellular damage exceeds the capacity of this adaptive response.

Porcine circovirus type 2 capsid protein induces unfolded protein response with subsequent activation of apoptosis

Porcine circovirus type 2（PCV2）has recently been reported to elicit the unfolded protein response（UPR）via activation of the PERK/e IF2α（RNA-activated protein kinase-like endoplasmic reticulum（ER）kinase/eukaryotic initiation factor 2α）pathway.This study attempted to examine which viral protein might be involved in inducing UPR and whether this cellular event would lead to apoptosis of the cells expressing the viral protein.By transient expression,we found that both replicase（Rep）and capsid（Cap）proteins of PCV2 could induce ER stress as shown by increased phosphorylation of PERK with subsequent activation of the eI F2α-ATF4（activating transcription factor 4）-CHOP（CCAAT/enhancer-binding protein homologous protein）axis.Cap expression,but not Rep,significantly reduced antiapoptotic B-cell lymphoma-2（Bcl-2）and increased caspase-3 cleavage,possibly due to increased expression of CHOP.Since knockdown of PERK by RNA interference clearly reduced Cap-induced CHOP expression,caspase-3cleavage,and apoptotic cell death possibly by partially rescuing Bcl-2 expression,we propose that there is connection between Cap-induced UPR and apoptosis via the PERK/eI F2α/ATF4/CHOP/Bcl-2 pathway.This study,together with our earlier studies,provides insight into the mechanisms underlying PCV2 pathogenesis.

Non-ionizing radiofrequency field induces unfolded protein response (UPR) in endoplasmic reticulum of mouse neuronal cells

Objective:To examine whether exposure of mouse neuronal cells to radiofrequency fields used in mobile communication devices can induce stress in endoplasmic reticulum(ER)and activate unfolded protein response(UPR).Methods:HT22 mouse hippocampus neuronal cells were exposed to continuous wave 900 MHz radiofrequency fields(RF)at 120μW/cm2 power intensity for 4 h/d for 5 consecutive days.The positive control cells were irradiated with 4 Gy of 60Coγ-rays at a dose rate of 0.5 Gy/min(GR).Twenty-four hours after the last exposure,cells were collected,and the expressions of sensor transmembrane proteins were detected using Western blot analysis.Results:The expression levels of Ire1,PERK,p-IRE1 and p-PERK,GRP78 and CHOP proteins were detected.There were no statistically significant differences in the expression levels of IRE1 and PERK proteins in control(CT),sham(SH)-,RF-and GR-exposed cells(P<0.05).The phosphorylated protein levels of p-IRE1 and p-PERK were significantly increased in cells exposed to RF and GR(P<0.05).The expression levels of GRP78 and CHOP were significantly increased in RF-and GR-exposed cells compared to CT and SH-exposed cells(P<0.05).Cells treated with 1μg/ml TM for 24 h showed significantly increased expression levels of GRP78 and CHOP proteins compared to controls(P<0.05).In the presence of 2 mmol/L PBA,TM-induced increased levels of GRP78 and CHOP proteins were reduced(P<0.05).Conclusions:The exposure of non-ionizing 900 MHz RF was able to cause stress in HT22 mouse neuronal cells and activated UPR in ER.Since UPR plays an important role in both cell survival(when UPR is mitigated)and apoptosis/death(under unresolvable stress conditions),further studies are required to determine the fate of the cells exposed to RF.

Regulation and function of endoplasmic reticulum autophagy in neurodegenerative diseases

The endoplasmic reticulum,a key cellular organelle,regulates a wide variety of cellular activities.Endoplasmic reticulum autophagy,one of the quality control systems of the endoplasmic reticulum,plays a pivotal role in maintaining endoplasmic reticulum homeostasis by controlling endoplasmic reticulum turnover,remodeling,and proteostasis.In this review,we briefly describe the endoplasmic reticulum quality control system,and subsequently focus on the role of endoplasmic reticulum autophagy,emphasizing the spatial and temporal mechanisms underlying the regulation of endoplasmic reticulum autophagy according to cellular requirements.We also summarize the evidence relating to how defective or abnormal endoplasmic reticulum autophagy contributes to the pathogenesis of neurodegenerative diseases.In summary,this review highlights the mechanisms associated with the regulation of endoplasmic reticulum autophagy and how they influence the pathophysiology of degenerative nerve disorders.This review would help researchers to understand the roles and regulatory mechanisms of endoplasmic reticulum-phagy in neurodegenerative disorders.

Mannogalactoglucan from mushrooms protects pancreatic islets via restoring UPR and promotes insulin secretion in TIDM mice

Type 1 diabetes mellitus(T1DM) lacks insulin secretion due to autoimmune deficiency of pancreaticβ-cells.Protecting pancreatic islets and enhancing insulin secretion has been therapeutic approaches.Mannogalactoglucan is the main type of polysaccharide from natural mushroom,which has potential medicinal prospects.Nevertheless,the antidiabetic property of mannogalactoglucan in T1DM has not been fully elucidated.In this study,we obtained the neutral fraction of alkali-soluble Armillaria mellea polysaccharide(AAMP-N) with the structure of mannogalactoglucan from the fruiting body of A.mellea and investigated the potential therapeutic value of AAMP-N in T1DM.We demonstrated that AAMP-N lowered blood glucose and improved diabetes symptoms in T1DM mice.AAMP-N activated unfolded protein response(UPR) signaling pathway to maintain ER protein folding homeostasis and promote insulin secretion in vivo.Besides that,AAMP-N promoted insulin synthesis via upregulating the expression of transcription factors,increased Ca^(2+) signals to stimulate intracellular insulin secretory vesicle transport via activating calcium/calmodulin-dependent kinase Ⅱ(CamkⅡ) and cAMP/PKA signals,and enhanced insulin secretory vesicle fusion with the plasma membrane via vesicle-associated membrane protein 2(VAMP2).Collectively,these studies demonstrated that the therapeutic potential of AAMP-N on pancreatic islets function,indicating that mannogalactoglucan could be natural nutraceutical used for the treatment of T1DM.

Knockdown of RCN1 contributes to the apoptosis of colorectal cancer via regulating IP3R1

Background:The incidence of colorectal cancer(CRC)has been increasing in recent years.Thus,the discovery of factors that can assist in alleviating CRC is urgently warranted.Methods:To identify a potential factor involved in the development of CRC,we screened the upregulated genes in tumor tissues through four datasets from an online database.The expression of reticulocalbin 1(RCN1),a Ca2+-binding protein,was upregulated in the four datasets.Based on loss-offunction experiments,the effect of RCN1 on cell viability was assessed by Cell Counting Kit-8(CCK-8)assay.The regulatory effect of RCN1 on apoptosis was evaluated through Annexin V-fluorescein 5-isothiocyanate(FITC)/propidium iodide(PI)staining assay and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling(TUNEL)assay in RKO and SW480 cells.Activation of endoplasmic reticulum(ER)stress signaling pathways was confirmed by estimating the phosphorylation and expression of PRKR-like ER kinase(PERK),inositol-requiring kinase-1(IRE1),transcription factor 6(ACT6),and CCAAT/enhancer-binding protein-homologous protein(CHOP).The intracellular Ca2+homeostasis regulated by RCN1 was determined through the detection of Ca2+concentration and mitochondrial membrane potential(MMP)measurement.Moreover,whether inositol 1,4,5-trisphosphate receptor type 1(IP3R1)was involved in the regulation of RCN1 in CRC was verified through the depletion of IP3R1 in RKO cells.Results:Knockdown of RCN1 reduced cell viability and facilitated apoptosis in RKO and SW480 cells.Phosphorylation of PERK and IRE1,activation of ATF6,and upregulation of CHOP were induced by the absence of RCN1,suggesting that the unfolded protein response(UPR)was activated in CRC cells.The concentration of Ca2+in mitochondria was increased after RCN1 depletion,followed by reduction in the MMP and release of cytochrome c from mitochondria to the cytoplasm in RKO and SW480 cells.Moreover,it was demonstrated that IP3R1 mediates the effect of RCN1 on apoptosis induced by ER stress in CRC cells.The downregulation of IP3R1 restored the RCN1 loss-induced apoptosis and the increased Ca2+concentration.Conclusion:Taken together,our results confirmed that silencing of RCN1 disrupted intracellular Ca2+homeostasis and promoted cell apoptosis caused by TG-induced ER stress by regulating IP3R1 and activating the UPR signaling pathways.

The Life of a Protein Molecule——Protein Quality Control

The research progress in molecular chaperones, unfolded protein response （UPR） and ER-associated degradation （ERAD） involved in the protein quality control was summarized in this paper, and then the existing problems and the future devel- opment prospect were also discussed. It was pointed out that the life process of protein experienced four stages including synthesizing, folding, assembling and degradation, while each stage required strict quality control. In endoplasmic reticulum （ER）, a variety of proteins had been synthesized, folded and modified to form func- tional proteins with certain conformation. When the folding was blocked in ER, the unfolded proteins would aggregate and induce the UPR, which up-regulated the level of modification enzymes folded by a series of molecular chaperones and proteins to help them accomplish folding and assembling. If these proteins were still folded incorrectly, they would enter into ERAD for being degraded.

A truncated protein product of the germline variant of the DUOX2 gene leads to adenomatous polyposis

Objective:In some patients with adenomatous polyposis,an identifiable pathogenic variant of known associated genes cannot be found.Researchers have studied this for decades;however,few new genes have been identified.Methods:Adenomatous polyposis coli(APC)negative polyposis patients were identified through next-generation sequencing and multiplex ligation-dependent probe amplification.Then,whole-exome sequencing(WES)was used to determine candidate genes harboring pathogenic variants.Functional experiments were performed to explore their effects.Subsequently,using Sanger sequencing,we found other polyposis patients carrying variants of the DUOX2 gene,encoding dual oxidase 2,and analyzed them.Results:From 88 patients with suspected familial adenomatous polyposis,25 unrelated APC negative polyposis patients were identified.Based on the WES results of 3 patients and 2 healthy relatives from a family,the germline nonsense variant(c.1588 A>T;p.K530 X)of the DUOX2 gene was speculated to play a decisive role in the pedigree in relation to adenomatous polyposis.During functional experiments,we observed that the truncated protein,h Duox2 K530,was overexpressed in the adenoma in a carrier of the DUOX2 nonsense variant,causing abnormal cell proliferation through endoplasmic reticulum(ER)retention.In addition,we found two unrelated APC negative patients carrying DUOX2 missense variants(c.3329 G>A,p.R1110 Q;c.4027 C>T,p.L1343 F).Given the results of the in silico analysis,these two missense variants might exert a negative influence on the function of h Duox2.Conclusions:To our knowledge,this is the first study that reports the possible association of DUOX2 germline variants with adenomatous polyposis.With an autosomal dominant inheritance,it causes ER retention,inducing an unfolded protein response.

Protein synthesis modulation as a therapeutic approach for amyotrophic lateral sclerosis and frontotemporal dementia

Protein synthesis is essential for cells to perform life metabolic processes.Pathological alterations of protein content can lead to particular diseases.Cells have an intrinsic array of mechanisms and pathways that are activated when protein misfolding,accumulation,aggregation or mislocalization occur.Some of them(like the unfolded protein response)represent complex interactions between endoplasmic reticulum sensors and elongation factors that tend to increase expression of chaperone proteins and/or repress translation in order to restore protein homeostasis(also known as proteostasis).This is even more important in neurons,as they are very susceptible to harmful effects associated with protein overload and proteostatic mechanisms are less effective with age.Several neurodegenerative pathologies such as Alzheimer’s,Parkinson’s,and Huntington’s diseases,amyotrophic lateral sclerosis and frontotemporal dementia exhibit a particular molecular signature of distinct,unbalanced protein overload.In amyotrophic lateral sclerosis and frontotemporal dementia,the majority of cases present intracellular inclusions of ubiquitinated transactive response DNA-binding protein of 43 kDa(TDP-43).TDP-43 is an RNA binding protein that participates in RNA metabolism,among other functions.Dysregulation of TDP-43(e.g.aggregation and mislocalization)can dramatically affect neurons,and this has been linked to disease development.Expression of amyotrophic lateral sclerosis/frontotemporal dementia TDP-43-related mutations in cellular and animal models has been shown to recapitulate key features of the amyotrophic lateral sclerosis/frontotemporal dementia disease spectrum.These variants can be causative of degeneration onset and progression.Most neurodegenerative diseases(including amyotrophic lateral sclerosis and frontotemporal dementia)have no cure at the moment;however,modulating translation has recently emerged as an attractive approach that can be performed at several steps(i.e.regulating activation of initiation and elongation factors,inhibiting unfolded protein response activation or inducing chaperone expression and activity).This review focuses on the features of protein imbalance in neurodegenerative disorders and the relevance of developing therapeutical compounds aiming at restoring proteostasis.We strive to highlight the importance of research on drugs that,not only restore protein imbalance without compromising translational activity of cells,but are also as safe as possible for the patients.

Reactive oxygen species-induced activation of Yes-associated protein-1 through the c-Myc pathway is a therapeutic target in hepatocellular carcinoma

BACKGROUND The Hippo signaling pathway regulates organ size by regulating cell proliferation and apoptosis with terminal effectors including Yes-associated protein-1(YAP-1).Dysregulation in Hippo pathway has been proposed as one of the therapeutic targets in hepatocarcinogenesis.The levels of reactive oxygen species(ROS)increase during the progression from early to advanced hepatocellular carcinoma(HCC).AIM To study the activation of YAP-1 by ROS-induced damage in HCC and the involved signaling pathway.METHODS The expression of YAP-1 in HCC cells(Huh-7,HepG2,and SNU-761)was quantified using real-time polymerase chain reaction and immunoblotting.Human HCC cells were treated with H2O2,which is a major component of ROS in living organisms,and with either YAP-1 small interfering RNA(siRNA)or control siRNA.To investigate the role of YAP-1 in HCC cells under oxidative stress,MTS assays were performed.Immunoblotting was performed to evaluate the signaling pathway responsible for the activation of YAP-1.Eighty-eight surgically resected frozen HCC tissue samples and 88 nontumor liver tissue samples were used for gene expression analyses.RESULTS H2O2 treatment increased the mRNA and protein expression of YAP-1 in HCC cells(Huh-7,HepG2,and SNU-761).Suppression of YAP-1 using siRNA transfection resulted in a significant decrease in tumor proliferation during H2O2 treatment both in vitro and in vivo(both P<0.05).The oncogenic action of YAP-1 occurred via the activation of the c-Myc pathway,leading to the upregulation of components of the unfolded protein response(UPR),including 78-kDa glucoseregulated protein and activating transcription factor-6(ATF-6).The YAP-1 mRNA levels in human HCC tissues were upregulated by 2.6-fold compared with those in nontumor tissues(P<0.05)and were positively correlated with the ATF-6 Levels(Pearson’s coefficient=0.299;P<0.05).CONCLUSION This study shows a novel connection between YAP-1 and the UPR through the c-Myc pathway during oxidative stress in HCC.The ROS-induced activation of YAP-1 via the c-Myc pathway,which leads to the activation of the UPR pathway,might be a therapeutic target in HCC.

Ultrastructural variation and key ER chaperones response induced by heat stress in intestinal cells of sea cucumber Apostichopus japonicus

Abstract The unfolded protein response(UPR)is an important protective and compensatory strategy used during endoplasmic reticulum stress caused by factors including glucose starvation,low pH,or heat shock.However,there is very little information on the possible role(s)of the UPR under adverse conditions experienced by marine invertebrates.We observed that rough endoplasmic reticulum(ER)was dramatically expanded and numerous autophagosomes were accumulated in the intestinal cells of sea cucumbers,Apostichopus japonicus,under heat stress(4 h at 25°C compared with 15°C controls).Moreover,heat stress led to sharp increases in the relative transcript and protein expression levels of two primary ER chaperones:the endoplasmic reticulum resident protein 29-like(ERP29)and protein disulfi de-isomerase A6-like(PDIA6).These results suggest a potential adaptive mechanism to deal with heat-induced stress in sea cucumber intestine.

Subversion of cellular stress responses by poxviruses

Cellular stress responses are powerful mechanisms that prevent and cope with the accumulation of macromolecular damage in the cells and also boost host defenses against pathogens. Cells can initiate either protective or destructive stress responses depending, to a large extent, on the nature and duration of the stressing stimulus as well as the cell type. The productive replication of a virus within a given cell places inordinate stress on the metabolism machinery of the host and, to assure the continuity of its replication, many viruses have developed ways to modulate the cell stress responses. Poxviruses are among the viruses that have evolved a large number of strategies to manipulate host stress responses in order to control cell fate and enhance their replicative success. Remarkably, nearly every step of the stress responses that is mounted during infection can be targeted by virally encoded functions. The fine-tuned interactions between poxviruses and the host stress responses has aided virologists to understand specific aspects of viral replication; has helped cell biologists to evaluate the role of stress signaling in the uninfected cell; and has tipped immunologists on how these signals contribute to alert the cells against pathogen invasionand boost subsequent immune responses. This review discusses the diverse strategies that poxviruses use to subvert host cell stress responses.