scholarly journals IRE1β negatively regulates IRE1α signaling in response to endoplasmic reticulum stress

2019 ◽  
Author(s):  
Michael J. Grey ◽  
Eva Cloots ◽  
Mariska S. Simpson ◽  
Nicole LeDuc ◽  
Yevgeniy V. Serebrenik ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Er Stress ◽  
Intestinal Epithelial Cells ◽  
Inhibitory Effect ◽  
Kinase Domain ◽  
Dominant Negative ◽  
Intestinal Epithelial ◽  
Stress Sensor ◽  
Mucosal Surfaces ◽  
The Unfolded Protein Response

ABSTRACTIRE1β is an ER stress sensor uniquely expressed in epithelial cells lining mucosal surfaces. Here, we show that intestinal epithelial cells expressing IRE1β have an attenuated response to ER stress. IRE1β assembles with and blocks activation of the closely related and most evolutionarily ancient stress-sensor IRE1α to suppress stress-induced xbp1 splicing, a key mediator of the unfolded protein response. In comparison, IRE1β has weak xbp1 splicing activity, largely explained by a non-conserved amino acid in the kinase domain that impairs its phosphorylation and restricts oligomerization. This enables IRE1β to act as a dominant negative suppressor of IRE1α. The inhibitory effect is amplified in cells by disrupting an XBP1-dependent feedback loop regulating stress-induced expression of IRE1α. Thus IRE1β functions to negatively regulate IRE1α signaling, perhaps enabling intestinal epithelial cells to manage the response to chronic stress stimuli at the host-environment interface.

scholarly journals IRE1β negatively regulates IRE1α signaling in response to endoplasmic reticulum stress

2020 ◽  
Vol 219 (2) ◽  
Author(s):  
Michael J. Grey ◽  
Eva Cloots ◽  
Mariska S. Simpson ◽  
Nicole LeDuc ◽  
Yevgeniy V. Serebrenik ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Kinase Domain ◽  
Dominant Negative ◽  
Hek293 Cells ◽  
Stress Sensor ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

IRE1β is an ER stress sensor uniquely expressed in epithelial cells lining mucosal surfaces. Here, we show that intestinal epithelial cells expressing IRE1β have an attenuated unfolded protein response to ER stress. When modeled in HEK293 cells and with purified protein, IRE1β diminishes expression and inhibits signaling by the closely related stress sensor IRE1α. IRE1β can assemble with and inhibit IRE1α to suppress stress-induced XBP1 splicing, a key mediator of the unfolded protein response. In comparison to IRE1α, IRE1β has relatively weak XBP1 splicing activity, largely explained by a nonconserved amino acid in the kinase domain active site that impairs its phosphorylation and restricts oligomerization. This enables IRE1β to act as a dominant-negative suppressor of IRE1α and affect how barrier epithelial cells manage the response to stress at the host–environment interface.

scholarly journals IRE1α-driven inflammation promotes clearance of Citrobacter rodentium infection

2021 ◽  
Author(s):  
Lydia A. Sweet ◽  
Sharon K. Kuss-Duerkop ◽  
A. Marijke Keestra-Gounder
Keyword(s):  
Epithelial Cells ◽  
Er Stress ◽  
Bacterial Infections ◽  
Intestinal Epithelial Cells ◽  
Small Animal ◽  
Intestinal Epithelial ◽  
Citrobacter Rodentium ◽  
Human Pathogens ◽  
Unfolded Protein ◽  
The Unfolded Protein Response

Endoplasmic reticulum (ER) stress is intimately linked with inflammation in response to pathogenic infections. ER stress occurs when cells experience a buildup of misfolded or unfolded protein during times of perturbation, such as infections, which facilitates the unfolded protein response (UPR). The UPR involves multiple host pathways in an attempt to re-establish homeostasis, which oftentimes leads to inflammation and cell death if unresolved. The UPR is activated to help resolve some bacterial infections, and the IRE1α pathway is especially critical in mediating inflammation. To understand the role of the IRE1α pathway of the UPR during enteric bacterial infection, we employed Citrobacter rodentium to study host-pathogen interactions in intestinal epithelial cells and the murine gastrointestinal (GI) tract. C. rodentium is an enteric mouse pathogen that is similar to the human pathogens enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC, respectively), which have limited small animal models. Here, we demonstrate that both C. rodentium and EPEC induced the UPR in intestinal epithelial cells. UPR induction during C. rodentium infection correlated with the onset of inflammation in bone marrow-derived macrophages (BMDMs). Our previous work implicated IRE1α and NOD1/2 in ER stress-induced inflammation, which we observed were also required for pro-inflammatory gene induction during C. rodentium infection. C. rodentium induced IRE1α-dependent inflammation in mice, and inhibiting IRE1α led to a dysregulated inflammatory response and delayed clearance of C. rodentium . This study demonstrates that ER stress aids inflammation and clearance of C. rodentium through a mechanism involving the IRE1α-NOD1/2 axis.

Inhibitory effect of carnosine on interleukin-8 production in intestinal epithelial cells through translational regulation

Cytokine ◽  
2008 ◽  
Vol 42 (2) ◽  
pp. 265-276 ◽  
Author(s):  
Dong Ok Son ◽  
Hideo Satsu ◽  
Yoshinobu Kiso ◽  
Mamoru Totsuka ◽  
Makoto Shimizu
Keyword(s):  
Epithelial Cells ◽  
Translational Regulation ◽  
Intestinal Epithelial Cells ◽  
Inhibitory Effect ◽  
Interleukin 8 ◽  
Intestinal Epithelial

Effects of Stearic Acid on Proliferation, Differentiation, Apoptosis, and Autophagy in Porcine Intestinal Epithelial Cells

2020 ◽  
Vol 20 (2) ◽  
pp. 157-166
Author(s):  
Yuan Yang ◽  
Jin Huang ◽  
Jianzhong Li ◽  
Huansheng Yang ◽  
Yulong Yin
Keyword(s):  
Cell Differentiation ◽  
Epithelial Cells ◽  
Stearic Acid ◽  
Er Stress ◽  
Intestinal Epithelial Cells ◽  
Dependent Manner ◽  
Intestinal Epithelial ◽  
High Concentrations ◽  
Induced Apoptosis ◽  
Dose Dependent

Background: Stearic acid (SA), a saturated long-chain fatty acid consisting of 18 carbon atoms, is widely found in feed ingredients, such as corn, soybeans, and wheat. However, the roles of SA in the renewal of intestinal epithelial cells remain unclear. Methods and Results: In the present study, we found that 0.01-0.1 mM SA promoted IPEC-J2 cell differentiation and did not affect IPEC-J2 cell viability. In addition, the results showed that the viability of IPEC-J2 cells was inhibited by SA in a time- and dose-dependent manner at high concentrations. Flow cytometry and western blot analysis suggested that SA induced apoptosis, autophagy and ER stress in cells. In addition, the amounts of triglyceride were significantly increased upon challenge with SA. Moreover, the decrease in the viability of cells induced by SA could be attenuated by 4-PBA, an inhibitor of ER stress. Conclusion: In summary, SA accelerated IPEC-J2 cell differentiation at 0.01-0.1 mM. Furthermore, SA induced IPEC-J2 cell apoptosis and autophagy by causing ER stress.

scholarly journals Enteropathogenic Escherichia coli Activates Ezrin, Which Participates in Disruption of Tight Junction Barrier Function

2001 ◽  
Vol 69 (9) ◽  
pp. 5679-5688 ◽  
Author(s):  
Ivana Simonovic ◽  
Monique Arpin ◽  
Athanasia Koutsouris ◽  
Holly J. Falk-Krzesinski ◽  
Gail Hecht
Keyword(s):  
Escherichia Coli ◽  
Epithelial Cells ◽  
Intestinal Epithelial Cells ◽  
Cytoskeletal Proteins ◽  
Dominant Negative ◽  
Intestinal Epithelial ◽  
E Coli ◽  
Membrane Cytoskeleton ◽  
Intestinal Pathogen ◽  
Response Expression

ABSTRACT Enteropathogenic Escherichia coli (EPEC) is an important human intestinal pathogen, especially in infants. EPEC adherence to intestinal epithelial cells induces the accumulation of a number of cytoskeletal proteins beneath the bacteria, including the membrane-cytoskeleton linker ezrin. Evidence suggests that ezrin can participate in signal transduction. The aim of this study was to determine whether ezrin is activated following EPEC infection and if it is involved in the cross talk with host intestinal epithelial cells. We show here that following EPEC attachment to intestinal epithelial cells there was significant phosphorylation of ezrin, first on threonine and later on tyrosine residues. A significant increase in cytoskeleton-associated ezrin occurred following phosphorylation, suggesting activation of this molecule. Nonpathogenic E. coli and EPEC strains harboring mutations in type III secretion failed to elicit this response. Expression of dominant-negative ezrin significantly decreased the EPEC-elicited association of ezrin with the cytoskeleton and attenuated the disruption of intestinal epithelial tight junctions. These results suggest that ezrin is involved in transducing EPEC-initiated signals that ultimately affect host physiological functions.

scholarly journals JunD enhances miR-29b levels transcriptionally and posttranscriptionally to inhibit proliferation of intestinal epithelial cells

2015 ◽  
Vol 308 (10) ◽  
pp. C813-C824 ◽  
Author(s):  
Tongtong Zou ◽  
Jaladanki N. Rao ◽  
Lan Liu ◽  
Lan Xiao ◽  
Hee Kyoung Chung ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Transcription Factor ◽  
Epithelial Cells ◽  
Transcriptional Activation ◽  
Binding Sites ◽  
Intestinal Epithelial Cells ◽  
Inhibitory Effect ◽  
Microrna Expression ◽  
Intestinal Epithelial ◽  
Gut Epithelium

Through its actions as component of the activating protein-1 (AP-1) transcription factor, JunD potently represses cell proliferation. Here we report a novel function of JunD in the regulation of microRNA expression in intestinal epithelial cells (IECs). Ectopically expressed JunD specifically increased the expression of primary and mature forms of miR-29b, whereas JunD silencing inhibited miR-29b expression. JunD directly interacted with the miR-29b1 promoter via AP-1-binding sites, whereas mutation of AP-1 sites from the miR-29b1 promoter prevented JunD-mediated transcriptional activation of the miR-29b1 gene. JunD also enhanced formation of the Drosha microprocessor complex, thus further promoting miR-29b biogenesis. Cellular polyamines were found to regulate miR-29b expression by altering JunD abundance, since the increase in miR-29b expression levels in polyamine-deficient cells was abolished by JunD silencing. In addition, miR-29b silencing prevented JunD-induced repression of IEC proliferation. Our findings indicate that JunD activates miR-29b by enhancing its transcription and processing, which contribute to the inhibitory effect of JunD on IEC growth and maintenance of gut epithelium homeostasis.

scholarly journals Endoplasmic Reticulum Stress and Intestinal Inflammation: A Perilous Union

2020 ◽  
Vol 11 ◽  
Author(s):  
Sanchez Preethi Eugene ◽  
Vadde Sudhakar Reddy ◽  
Jamma Trinath
Keyword(s):  
Endoplasmic Reticulum ◽  
Epithelial Cells ◽  
Er Stress ◽  
Lamina Propria ◽  
Immune Cells ◽  
Intestinal Inflammation ◽  
Intestinal Epithelial Cells ◽  
Pharmacological Intervention ◽  
Intestinal Epithelial ◽  
Exogenous Origin

The intestinal tract encompasses the largest mucosal surface fortified with a fine layer of intestinal epithelial cells along with highly sophisticated network of the lamina propria immune cells that are indispensable to sustain gut homeostasis. However, it can be challenging to uphold homeostasis when these cells in the intestine are perpetually exposed to insults of both endogenous and exogenous origin. The complex networking and dynamic microenvironment in the intestine demand highly functional cells ultimately burdening the endoplasmic reticulum (ER) leading to ER stress. Unresolved ER stress is one of the primary contributors to the pathogenesis of inflammatory bowel diseases (IBD). Studies also suggest that ER stress can be the primary cause of inflammation and/or the consequence of inflammation. Therefore, understanding the patterns of expression of ER stress regulators and deciphering the intricate interplay between ER stress and inflammatory pathways in intestinal epithelial cells in association with lamina propria immune cells contribute toward the development of novel therapies to tackle IBD. This review provides imperative insights into the molecular markers involved in the pathogenesis of IBD by potentiating ER stress and inflammation and briefly describes the potential pharmacological intervention strategies to mitigate ER stress and IBD. In addition, genetic mutations in the biomarkers contributing to abnormalities in the ER stress signaling pathways further emphasizes the relevance of biomarkers in potential treatment for IBD.

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