Endoplasmic reticulum stress in the regulation of liver diseases: Involvement of Regulated IRE1<b>α</b> and <b>β</b>‐dependent decay and miRNA

Rashid, Harunor; Kim, Hyun-Kyoung; Junjappa, Raghupatil; Kim, Hyung‐Ryong; Chae, Han-Jung

doi:10.1111/jgh.13619

Cited by 18 publications

(8 citation statements)

References 69 publications

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“…XBP1s upregulates the expression of many genes related to UPR, including ZNF64, GPR7, PLK, and MRPS22 (Ron and Walter, 2007;Peschek et al, 2015), to increase the expression of chaperones and foldase to mitigate ERS. In addition, under persistent and unresolved ERS, XBP1s can initiate a global mRNA degradation to limit the translation of proteins on the ER -a process known as regulated IRE1αdependent decay, which ultimately induces ER destruction and apoptosis (Tam et al, 2014;Rashid et al, 2017). In bladder cancer, upregulated IRE1α is associated with an immediate UPR to restore protein homeostasis, and if UPR fails to alleviate ERS under prolonged or severe ERS, cells activate apoptosis pathways to eliminate damaged cells (Wu et al, 2019a).…”

Section: Ire1α Pathwaymentioning

confidence: 99%

Endoplasmic Reticulum Stress and Tumor Microenvironment in Bladder Cancer: The Missing Link

Nie

Chen

Wen

et al. 2021

Front. Cell Dev. Biol.

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Bladder cancer is a common malignant tumor of the urinary system. Despite recent advances in treatments such as local or systemic immunotherapy, chemotherapy, and radiotherapy, the high metastasis and recurrence rates, especially in muscle-invasive bladder cancer (MIBC), have led to the evaluation of more targeted and personalized approaches. A fundamental understanding of the tumorigenesis of bladder cancer along with the development of therapeutics to target processes and pathways implicated in bladder cancer has provided new avenues for the management of this disease. Accumulating evidence supports that the tumor microenvironment (TME) can be shaped by and reciprocally act on tumor cells, which reprograms and regulates tumor development, metastasis, and therapeutic responses. A hostile TME, caused by intrinsic tumor attributes (e.g., hypoxia, oxidative stress, and nutrient deprivation) or external stressors (e.g., chemotherapy and radiation), disrupts the normal synthesis and folding process of proteins in the endoplasmic reticulum (ER), culminating in a harmful situation called ER stress (ERS). ERS is a series of adaptive changes mediated by unfolded protein response (UPR), which is interwoven into a network that can ultimately mediate cell proliferation, apoptosis, and autophagy, thereby endowing tumor cells with more aggressive behaviors. Moreover, recent studies revealed that ERS could also impede the efficacy of anti-cancer treatment including immunotherapy by manipulating the TME. In this review, we discuss the relationship among bladder cancer, ERS, and TME; summarize the current research progress and challenges in overcoming therapeutic resistance; and explore the concept of targeting ERS to improve bladder cancer treatment outcomes.

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Section: Ire1α Pathwaymentioning

confidence: 99%

Endoplasmic Reticulum Stress and Tumor Microenvironment in Bladder Cancer: The Missing Link

Nie

Chen

Wen

et al. 2021

Front. Cell Dev. Biol.

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“…Small-molecule IRE1 modulators provide important tools to probe the physiology of IRE1 in both healthy state and disease. Selective IRE1 RNase activation, in particular, has not been extensively explored, despite recent studies showing that this approach may have therapeutic potential for certain metabolic disorders [22][23][24] , cancers 25 , viral infections 26,27 , protein aggregation pathologies 28 , and neurodegenerative diseases 29 . To date, the best-characterized allosteric activators are APY29 10 , IPA 21 , and CRUK-3 30 .…”

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confidence: 99%

Activation of the IRE1 RNase through remodeling of the kinase front pocket by ATP-competitive ligands

Ferri¹,

Thomas

Wallweber³

et al. 2020

Nat Commun

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Inositol-Requiring Enzyme 1 (IRE1) is an essential component of the Unfolded Protein Response. IRE1 spans the endoplasmic reticulum membrane, comprising a sensory lumenal domain, and tandem kinase and endoribonuclease (RNase) cytoplasmic domains. Excess unfolded proteins in the ER lumen induce dimerization and oligomerization of IRE1, triggering kinase trans-autophosphorylation and RNase activation. Known ATP-competitive small-molecule IRE1 kinase inhibitors either allosterically disrupt or stabilize the active dimeric unit, accordingly inhibiting or stimulating RNase activity. Previous allosteric RNase activators display poor selectivity and/or weak cellular activity. In this study, we describe a class of ATP-competitive RNase activators possessing high selectivity and strong cellular activity. This class of activators binds IRE1 in the kinase front pocket, leading to a distinct conformation of the activation loop. Our findings reveal exquisitely precise interdomain regulation within IRE1, advancing the mechanistic understanding of this important enzyme and its investigation as a potential small-molecule therapeutic target.

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“…On the one hand, ER stress response was mediated by three transmembrane proteins: inositol requiring enzyme-1α, PKR-like ER kinase, and activating transcription factor 6. The major ER chaperone GRP78 could regulate ER stress via binding ER luminal domain and cytosolic signal-transduction domain of three proteins and modulate related signaling pathways, respectively ( Malhi and Kaufman, 2011 ; Hernandez-Gea et al, 2013 ; Koo et al, 2016 ; Navid and Colbert, 2017 ; Rashid et al, 2017 ). On the other hand, ER stress could lead to cell death by inducing apoptosis ( Breckenridge et al, 2003 ; Rutkowski and Kaufman, 2004 ).…”

Section: Discussionmentioning

confidence: 99%

Ufbp1, a Key Player of Ufm1 Conjugation System, Protects Against Ketosis-Induced Liver Injury via Suppressing Smad3 Activation

Chen

Shen

et al. 2021

Front. Cell Dev. Biol.

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The dairy cattle suffer from severe liver dysfunction during the pathogenesis of ketosis. The Ufm1 conjugation system is crucial for liver development and homeostasis. Ufm1 binding protein (Ufbp1) is a putative Ufm1 target and an integral component, but its role in ketosis-induced liver injury is unclear so far. The purpose of this study is to explore the key role of Ufbp1 in liver fibrosis caused by ketosis in vivo and in vitro. Liver tissues were collected from ketotic cows and Ufbp1 conditional knockout (CKO) mice in vivo. However, Ufbp1–/– mouse embryonic fibroblast cells and Hela cells were used for in vitro validation. Subsequently, various assays were performed to reveal the underlying molecular mechanisms of the Ufbp1 protective effect. In this study, hepatic fibrosis, endoplasmic reticulum (ER) stress, and apoptosis were reported in the liver of ketotic cows, fibrotic markers (alpha-smooth muscle actin, Collagen1) and ER stress markers (glucose-regulated protein 78, CEBP homologous protein) were upregulated remarkably, and the apoptosis-related genes (Bcl2, Bax) were in line with expectations. Interestingly, Ufbp1 expression was almost disappeared, and Smad2/Smad3 protein was largely phosphorylated in the liver of ketotic cows, but Ufbp1 deletion caused Smad3 phosphorylation apparently, rather than Smad2, and elevated ER stress was observed in the CKO mice model. At the cellular level, Ufbp1 deficiency led to serious fibrotic and ER stress response, Smad3 was activated by phosphorylation significantly and then was translocated into the nucleus, whereas p-Smad2 was largely unaffected in embryonic fibroblast cells. Ufbp1 overexpression obviously suppressed Smad3 phosphorylation in Hela cells. Ufbp1 was found to be in full combination with Smad3 using endogenous immunoprecipitation. Taken together, our findings suggest that downregulation or ablation of Ufbp1 leads to Smad3 activation, elevated ER stress, and hepatocyte apoptosis, which in turn causes liver fibrosis. Ufbp1 plays a protective role in ketosis-induced liver injury.

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Endoplasmic reticulum stress in the regulation of liver diseases: Involvement of Regulated IRE1α and β‐dependent decay and miRNA

Cited by 18 publications

References 69 publications

Endoplasmic Reticulum Stress and Tumor Microenvironment in Bladder Cancer: The Missing Link

Endoplasmic Reticulum Stress and Tumor Microenvironment in Bladder Cancer: The Missing Link

Activation of the IRE1 RNase through remodeling of the kinase front pocket by ATP-competitive ligands

Ufbp1, a Key Player of Ufm1 Conjugation System, Protects Against Ketosis-Induced Liver Injury via Suppressing Smad3 Activation

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