Role of Endoplasmic Reticulum Stress Sensor IRE1α in Cellular Physiology, Calcium, ROS Signaling, and Metaflammation

Riaz, Thoufiqul Alam; Junjappa, Raghu Patil; Handigund, Mallikarjun; Ferdous, Jannatul; Kim, Hyung‐Ryong; Chae, Han-Jung

doi:10.3390/cells9051160

Cited by 62 publications

(61 citation statements)

References 248 publications

(240 reference statements)

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“…Studies have shown that IRE1α plays an important role in mediating ROS-generation ( Abuaita et al, 2015 ) and 4μ8C has been described as a potent ROS-scavenger ( Chan et al, 2018 ). IRE1α generates ROS through Ca 2+ -mediated signaling between the IRE1α-InsP3R pathway in the ER and the redox-dependent apoptotic pathway in the mitochondrion, as well as via activation of CHOP, BIP and through XBP1-splicing ( Riaz et al, 2020 ; Zeeshan et al, 2016 ). In line with these findings, we found a significant reduction in intracellular ROS-levels after treatment with 4μ8C in LX2, HepG2 and Huh7-cells.…”

Section: Discussionmentioning

confidence: 99%

Inhibiting IRE1α-endonuclease activity decreases tumor burden in a mouse model for hepatocellular carcinoma

Pavlović

Calitz

Thanapirom

et al. 2020

eLife

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Hepatocellular carcinoma (HCC) is a liver tumor that usually arises in patients with cirrhosis. Hepatic stellate cells are key players in the progression of HCC, as they create a fibrotic micro-environment and produce growth factors and cytokines that enhance tumor cell proliferation and migration. We assessed the role of endoplasmic reticulum (ER) stress in the cross-talk between stellate cells and HCC-cells. Mice with a fibrotic HCC were treated with the IRE1α-inhibitor 4μ8C, which reduced tumor burden and collagen deposition. By co-culturing HCC-cells with stellate cells, we found that HCC-cells activate IREα in stellate cells, thereby contributing to their activation. Inhibiting IRE1α blocked stellate cell activation, which then decreased proliferation and migration of tumor cells in different in vitro 2D and 3D co-cultures. In addition, we also observed cell-line specific direct effects of inhibiting IRE1α in tumor cells.

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Section: Discussionmentioning

confidence: 99%

Inhibiting IRE1α-endonuclease activity decreases tumor burden in a mouse model for hepatocellular carcinoma

Pavlović

Calitz

Thanapirom

et al. 2020

eLife

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“…It is involved not only in neurodegenerative diseases but also in obesity, in ammation and T2DM, among others. Therefore, its inhibition could offer an interesting avenue for AD (91)(92)(93). Going further, ATF3 is a stress-induced and adaptive-responsive gene located downstream of eIF2α which basal levels are low.…”

Section: Discussionmentioning

confidence: 99%

Dexibuprofen ameliorates peripheral and central risk factors associated with Alzheimer’s disease in metabolically stressed APPswe/PS1dE9 mice

Ettcheto

Cano

Carrasco

et al. 2021

Preprint

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Background: Several studies stablished a relationship between metabolic disturbances and Alzheimer´s disease (AD) where inflammation plays a pivotal role. However, mechanisms involved still remain unclear. In the present study, we aimed to evaluate central and peripheral effects of dexibuprofen (DXI) in the progression of AD in APPswe/PS1dE9 (APP/PS1) female mice, a familial AD model, fed with high fat diet (HFD). Animals were fed either with conventional chow or with HFD, from their weaning until their sacrifice, at 6 months. Moreover, mice were divided into subgroups to which were administered drinking water or water supplemented with DXI (20mg·kg-1·d-1) for 3 months. Before sacrifice, body weight, intraperitoneal glucose and insulin tolerance test (IP-ITT) were performed to evaluate peripheral parameters and also behavioral tests to determine cognitive decline. Moreover, molecular studies such as Western blot and RT-PCR were carried out in liver to confirm metabolic effects and in hippocampus to analyze several pathways considered hallmarks in AD. Results: Our studies demonstrate that DXI improved metabolic alterations observed in transgenic animals fed with HFD in vivo, data in accordance with those obtained at molecular level. Moreover, an improvement of cognitive decline and neuroinflammation among other pathways associated with AD were observed such as beta-amyloid plaque accumulation and unfolded protein response.Conclusions: Collectively, evidence suggest that chronic administration of DXI prevents the progression of AD through the regulation of inflammation which contribute to improve hallmarks of this pathology. Thus, this compound could constitute a novel therapeutic approach in the treatment of AD in a combined therapy.

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“…IRE1α is a multi-functional protein (Riaz et al, 2020), we wanted to examine the importance of IRE1α in PA induced CIK cell inflammation and autophagy, CIK cells were exposed to PA, with or without 4μ8c. As shown in Fig.…”

Section: Inhibition Of Ire1α Ameliorates Pa Induced Autophagy and Infmentioning

confidence: 99%

Molecular characterization of ER Stress sensor IRE1α and IRE1β and their expression analysis in response to different fatty acid in grass carp (Ctenopharyngodon idellus)

Chang

Yang

2021

Preprint

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Inositol-requiring enzyme 1 (IRE1) is the most evolutionarily conserved endoplasmic reticulum (ER) membrane protein. Here, we identified and analyzed two IRE isoforms (IRE1α and IRE1β) in grass carp ( Ctenopharyngodon idellus ). The coding sequences of IRE1α and IRE1β were 3096 and 2835 nucleotides, and they encoded proteins of 1031 and 944 amino acids, respectively. Each of the two IRE1s proteins had four PPQ domains, a transmembrane helix region, an S_TKc and a PUG domain, which were relatively conserved in comparison to mammals. qRT-PCR revealed that IRE1α was the highest in liver and brain, whereas the highest expression of IRE1β expressed was found in the hindgut, which may be closely related with their role. Moreover, we have compared the effect of saturated (palmitic acid, PA) , monounsaturated fatty acid (oleic acid, OA) and polyunsaturated fatty acids (Docosahexaenoic acid, DHA) on ER stress in CIK cells, and found that PA and DHA induced UPR-related gene expression in dose-dependent , and OA increased expression of IRE1α and decreased expression of IRE1β, ATF4 and ATF6 at lower doses. Additionally, our studies revealed that blocking IRE1α pathway using specific inhibitor 4μ8c, subsequently reversed PA-induced autophagy and inflammation, indicating the role of IRE1α in mediating PA-induced CIK cells. Taken together, the study demonstrated the IRE1α and IRE1β that likely have an important role in physiological processes induced by fatty acids in grass carp.

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Role of Endoplasmic Reticulum Stress Sensor IRE1α in Cellular Physiology, Calcium, ROS Signaling, and Metaflammation

Cited by 62 publications

References 248 publications

Inhibiting IRE1α-endonuclease activity decreases tumor burden in a mouse model for hepatocellular carcinoma

Inhibiting IRE1α-endonuclease activity decreases tumor burden in a mouse model for hepatocellular carcinoma

Dexibuprofen ameliorates peripheral and central risk factors associated with Alzheimer’s disease in metabolically stressed APPswe/PS1dE9 mice

Molecular characterization of ER Stress sensor IRE1α and IRE1β and their expression analysis in response to different fatty acid in grass carp (Ctenopharyngodon idellus)

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