F-actin and a Type-II Myosin Are Required for Efficient Clustering of the ER Stress Sensor Ire1

Inositol-requiring transmembrane kinase endoribonuclease-1α (IRE1α) is the most prominent and evolutionarily conserved unfolded protein response (UPR) signal transducer during endoplasmic reticulum functional upset (ER stress). A IRE1α signal pathway arbitrates yin and yang of cellular fate in objectionable conditions. It plays several roles in fundamental cellular physiology as well as in several pathological conditions such as diabetes, obesity, inflammation, cancer, neurodegeneration, and in many other diseases. Thus, further understanding of its molecular structure and mechanism of action during different cell insults helps in designing and developing better therapeutic strategies for the above-mentioned chronic diseases. In this review, recent insights into structure and mechanism of activation of IRE1α along with its complex regulating network were discussed in relation to their basic cellular physiological function. Addressing different binding partners that can modulate IRE1α function, UPRosome triggers different downstream pathways depending on the cellular backdrop. Furthermore, IRE1α are in normal cell activities outside the dominion of ER stress and activities under the weather of inflammation, diabetes, and obesity-related metaflammation. Thus, IRE1 as an ER stress sensor needs to be understood from a wider perspective for comprehensive functional meaning, which facilitates us with assembling future needs and therapeutic benefits.

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Japanese Encephalitis Virus Induces Apoptosis and Encephalitis by Activating the PERK Pathway

Journal of Virology ◽

10.1128/jvi.00887-19 ◽

2019 ◽

Vol 93 (17) ◽

Cited By ~ 6

Author(s):

Qianruo Wang ◽

Xiu Xin ◽

Ting Wang ◽

Jiawu Wan ◽

Yangtao Ou ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Japanese Encephalitis Virus ◽

Japanese Encephalitis ◽

Encephalitis Virus ◽

Protein Kinase R ◽

Apoptosis Pathway ◽

Stress Sensor ◽

Sensor Protein ◽

Induced Apoptosis

ABSTRACTAccumulated evidence demonstrates that Japanese encephalitis virus (JEV) infection triggers endoplasmic reticulum (ER) stress and neuron apoptosis. ER stress sensor protein kinase R-like endoplasmic reticulum kinase (PERK) has been reported to induce apoptosis under acute or prolonged ER stress. However, the precise role of PERK in JEV-induced apoptosis and encephalitis remains unknown. Here, we report that JEV infection activates the PERK-ATF4-CHOP apoptosis pathway bothin vitroandin vivo. PERK activation also promotes the formation of stress granule, which in turn represses JEV-induced apoptosis. However, PERK inhibitor reduces apoptosis, indicating that JEV-activated PERK predominantly induces apoptosis via the PERK-ATF4-CHOP apoptosis pathway. Among JEV proteins that have been reported to induce ER stress, only JEV NS4B can induce PERK activation. PERK has been reported to form an active molecule by dimerization. The coimmunoprecipitation assay shows that NS4B interacts with PERK. Moreover, glycerol gradient centrifugation shows that NS4B induces PERK dimerization. Both the LIG-FHA and the LIG-WD40 domains within NS4B are required to induce PERK dimerization, suggesting that JEV NS4B pulls two PERK molecules together by simultaneously interacting with them via different motifs. PERK deactivation reduces brain cell damage and encephalitis during JEV infection. Furthermore, expression of JEV NS4B is sufficient to induce encephalitis via PERK in mice, indicating that JEV activates PERK primarily via its NS4B to cause encephalitis. Taken together, our findings provide a novel insight into JEV-caused encephalitis.IMPORTANCEJapanese encephalitis virus (JEV) infection triggers endoplasmic reticulum (ER) stress and neuron apoptosis. ER stress sensor protein kinase R-like endoplasmic reticulum kinase (PERK) has been reported to induce apoptosis under acute or prolonged ER stress. However, whether the PERK pathway of ER stress response plays important roles in JEV-induced apoptosis and encephalitis remains unknown. Here, we found that JEV infection activates ER stress sensor PERK in neuronal cells and mouse brains. PERK activation induces apoptosis via the PERK-ATF4-CHOP apoptosis pathway upon JEV infection. Among the JEV proteins prM, E, NS1, NS2A, NS2B, and NS4B, only NS4B activates PERK. Moreover, activated PERK participates in apoptosis and encephalitis induced by JEV and NS4B. These findings provide a novel therapeutic approach for JEV-caused encephalitis.

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Pre-S2 Mutant-Induced Mammalian Target of Rapamycin Signal Pathways as Potential Therapeutic Targets for Hepatitis B Virus-Associated Hepatocellular Carcinoma

Cell Transplantation ◽

10.3727/096368916x694382 ◽

2017 ◽

Vol 26 (3) ◽

pp. 429-438 ◽

Cited By ~ 11

Author(s):

Chiao-Fang Teng ◽

Han-Chieh Wu ◽

Woei-Cherng Shyu ◽

Long-Bin Jeng ◽

Ih-Jen Su

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Er Stress ◽

Mammalian Target Of Rapamycin ◽

Hbv Infection ◽

Target Of Rapamycin ◽

Signal Pathways ◽

Type Ii ◽

B Virus

Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). Pre-S2 mutant represents an HBV oncoprotein that is accumulated in the endoplasmic reticulum (ER) and manifests as type II ground glass hepatocytes (GGHs). Pre-S2 mutant can induce ER stress and initiate multiple ER stress-dependent or -independent cellular signal pathways, leading to growth advantage of type II GGH. Importantly, the mammalian target of rapamycin (mTOR) signal pathways are consistently activated throughout the liver tumorigenesis in pre-S2 mutant transgenic mice and in human HCC tissues, leading to hepatocyte proliferation, metabolic disorders, and HCC tumorigenesis. In this review, we summarize the pre-S2 mutant-induced mTOR signal pathways and its implications in HBV-related HCC tumorigenesis. Clinically, the presence of pre-S2 mutant exhibits a high resistance to antiviral treatment and carries a high risk of HCC development in patients with chronic HBV infection. Targeting at pre-S2 mutant-induced mTOR signal pathways may thus provide potential strategies for the prevention or therapy of HBV-associated HCC.

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Activation of endoplasmic reticulum stress mediates oxidative stress–induced apoptosis of granulosa cells in ovaries affected by endometrioma

MHR Basic science of reproductive medicine ◽

10.1093/molehr/gaz066 ◽

2019 ◽

Vol 26 (1) ◽

pp. 40-52 ◽

Cited By ~ 2

Author(s):

Chisato Kunitomi ◽

Miyuki Harada ◽

Nozomi Takahashi ◽

Jerilee M K Azhary ◽

Akari Kusamoto ◽

...

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Granulosa Cells ◽

Ovarian Function ◽

Stress Sensor ◽

Local Factor ◽

High Oxidative Stress ◽

Induced Apoptosis ◽

Sensor Proteins

Abstract Endometriosis exerts detrimental effects on ovarian physiology and compromises follicular health. Granulosa cells from patients with endometriosis are characterized by increased apoptosis, as well as high oxidative stress. Endoplasmic reticulum (ER) stress, a local factor closely associated with oxidative stress, has emerged as a critical regulator of ovarian function. We hypothesized that ER stress is activated by high oxidative stress in granulosa cells in ovaries with endometrioma and that this mediates oxidative stress–induced apoptosis. Human granulosa-lutein cells (GLCs) from patients with endometrioma expressed high levels of mRNAs associated with the unfolded protein response (UPR). In addition, the levels of phosphorylated ER stress sensor proteins, inositol-requiring enzyme 1 (IRE1) and double-stranded RNA-activated protein kinase-like ER kinase (PERK), were elevated in granulosa cells from patients with endometrioma. Given that ER stress results in phosphorylation of ER stress sensor proteins and induces UPR factors, these findings indicate that these cells were under ER stress. H2O2, an inducer of oxidative stress, increased expression of UPR-associated mRNAs in cultured human GLCs, and this effect was abrogated by pretreatment with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor in clinical use. Treatment with H2O2 increased apoptosis and the activity of the pro-apoptotic factors caspase-8 and caspase-3, both of which were attenuated by TUDCA. Our findings suggest that activated ER stress induced by high oxidative stress in granulosa cells in ovaries with endometrioma mediates apoptosis of these cells, leading to ovarian dysfunction in patients with endometriosis.

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Su1094 THE ER STRESS SENSOR IRE1β LINKS EPITHELIAL DIFFERENTIATION AND HOST-MICROBIOTA INTERACTIONS TO PROTECT AGAINST COLITIS

Gastroenterology ◽

10.1016/s0016-5085(20)31946-6 ◽

2020 ◽

Vol 158 (6) ◽

pp. S-507

Author(s):

Michael J. Grey ◽

Heidi De Luca ◽

Jay R. Thiagarajah ◽

Jerrold Turner ◽

Wayne I. Lencer

Keyword(s):

Er Stress ◽

Epithelial Differentiation ◽

Stress Sensor

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Transcriptomic Analysis Identifies Pathways Mediating Alveolar Epithelial Type II (AT2) Cell Dysfunction and Fibrosis in Response to ER Stress Following Grp78 Knockout (KO)

10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a7233 ◽

2019 ◽

Author(s):

B. Zhou ◽

M. Horie ◽

P. Flodby ◽

H. Wang ◽

Y. Liu ◽

...

Keyword(s):

Er Stress ◽

Transcriptomic Analysis ◽

Type Ii ◽

Alveolar Epithelial ◽

Cell Dysfunction

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Transdifferentiation mediated tumor suppression by the endoplasmic reticulum stress sensor IRE-1 in C. elegans

eLife ◽

10.7554/elife.08005 ◽

2015 ◽

Vol 4 ◽

Cited By ~ 4

Author(s):

Mor Levi-Ferber ◽

Hai Gian ◽

Reut Dudkevich ◽

Sivan Henis-Korenblit

Keyword(s):

Tumor Cell ◽

Er Stress ◽

Tumor Progression ◽

Tumor Cells ◽

Tumor Therapy ◽

Tumor Model ◽

Apoptosis Resistance ◽

Stress Sensor ◽

C Elegans ◽

Cell Transdifferentiation

Deciphering effective ways to suppress tumor progression and to overcome acquired apoptosis resistance of tumor cells are major challenges in the tumor therapy field. We propose a new concept by which tumor progression can be suppressed by manipulating tumor cell identity. In this study, we examined the effect of ER stress on apoptosis resistant tumorous cells in a Caenorhabditis elegans germline tumor model. We discovered that ER stress suppressed the progression of the lethal germline tumor by activating the ER stress sensor IRE-1. This suppression was associated with the induction of germ cell transdifferentiation into ectopic somatic cells. Strikingly, transdifferentiation of the tumorous germ cells restored their ability to execute apoptosis and enabled their subsequent removal from the gonad. Our results indicate that tumor cell transdifferentiation has the potential to combat cancer and overcome the escape of tumor cells from the cell death machinery.

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