scholarly journals The epithelial-specific ER stress sensor IRE1β enables host-microbiota crosstalk to affect colon goblet cell development

2021 ◽  
Author(s):  
Michael J. Grey ◽  
Heidi De Luca ◽  
Doyle V. Ward ◽  
Irini A. M. Kreulen ◽  
Sage E. Foley ◽  
...  
Keyword(s):  
Er Stress ◽  
Goblet Cell ◽  
Alimentary Tract ◽  
Cell Development ◽  
Stress Sensor ◽  
Germ Free ◽  
Mucosal Surfaces ◽  
Xbp1 Mrna ◽  
Evolutionarily Conserved ◽  
Mucus Barrier

Epithelial cells lining mucosal surfaces of the gastrointestinal and respiratory tracts uniquely express IRE1β (Ern2), a paralogue of the most evolutionarily conserved endoplasmic reticulum stress sensor IRE1α. How IRE1β functions at the host-environment interface and why a second IRE1 paralogue evolved remain incompletely understood. Using conventionally raised and germ-free Ern2-/- mice, we found that IRE1β was required for microbiota-induced goblet cell maturation and mucus barrier assembly in the colon. This occurred only after colonization of the alimentary tract with normal gut microflora, which induced IRE1β expression. IRE1β acted by splicing Xbp1 mRNA to expand ER function and prevent ER stress in goblet cells. Although IRE1α can also splice Xbp1 mRNA, it did not act redundantly to IRE1β in this context. By regulating assembly of the colon mucus layer, IRE1β further shaped the composition of the gut microbiota. Mice lacking IRE1β had a dysbiotic microbial community that failed to induce goblet cell development when transferred into germ-free wild type mice. These results show that IRE1β evolved at mucosal surfaces to mediate crosstalk between gut microbes and the colonic epithelium required for normal homeostasis and host defense.

scholarly journals Evolution and function of the epithelial cell-specific ER stress sensor IRE1β

2021 ◽  
Author(s):  
Eva Cloots ◽  
Mariska S. Simpson ◽  
Clint De Nolf ◽  
Wayne I. Lencer ◽  
Sophie Janssens ◽  
...  
Keyword(s):  
Er Stress ◽  
Specific Expression ◽  
Stress Sensor ◽  
Mucosal Tissues ◽  
Mucosal Surfaces ◽  
Evolutionarily Conserved ◽  
Host Defense Response ◽  
Mucosal Homeostasis ◽  
Mucus Barrier ◽  
And Function

AbstractBarrier epithelial cells lining the mucosal surfaces of the gastrointestinal and respiratory tracts interface directly with the environment. As such, these tissues are continuously challenged to maintain a healthy equilibrium between immunity and tolerance against environmental toxins, food components, and microbes. An extracellular mucus barrier, produced and secreted by the underlying epithelium plays a central role in this host defense response. Several dedicated molecules with a unique tissue-specific expression in mucosal epithelia govern mucosal homeostasis. Here, we review the biology of Inositol-requiring enzyme 1β (IRE1β), an ER-resident endonuclease and paralogue of the most evolutionarily conserved ER stress sensor IRE1α. IRE1β arose through gene duplication in early vertebrates and adopted functions unique from IRE1α which appear to underlie the basic development and physiology of mucosal tissues.

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

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1160 ◽  
Author(s):  
Thoufiqul Alam Riaz ◽  
Raghu Patil Junjappa ◽  
Mallikarjun Handigund ◽  
Jannatul Ferdous ◽  
Hyung-Ryong Kim ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Stress Sensor ◽  
Cellular Physiology ◽  
Unfolded Protein ◽  
Therapeutic Benefits ◽  
Evolutionarily Conserved ◽  
Yin And Yang ◽  
Protein Response ◽  
Diabetes And Obesity

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.

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 Intestinal Goblet Cell Loss during Chorioamnionitis in Fetal Lambs: Mechanistic Insights and Postnatal Implications

2021 ◽  
Vol 22 (4) ◽  
pp. 1946
Author(s):  
Charlotte van Gorp ◽  
Ilse H. de Lange ◽  
Kimberly R. I. Massy ◽  
Lilian Kessels ◽  
Alan H. Jobe ◽  
...  
Keyword(s):  
Er Stress ◽  
Goblet Cell ◽  
Intestinal Inflammation ◽  
Cell Loss ◽  
Goblet Cells ◽  
Premature Delivery ◽  
Cell Numbers ◽  
Cell Counts ◽  
Cell Alterations ◽  
Mucus Barrier

Chorioamnionitis, an important cause of preterm birth, is linked to necrotizing enterocolitis (NEC). NEC is characterized by a disrupted mucus barrier, goblet cell loss, and endoplasmic reticulum (ER) stress of the intestinal epithelium. These findings prompted us to investigate the mechanisms underlying goblet cell alterations over time in an ovine chorioamnionitis model. Fetal lambs were intra-amniotically (IA) exposed to lipopolysaccharides (LPS) for 5, 12, or 24 h, or 2, 4, 8, or 15 d before premature delivery at 125 d gestational age (GA). Gut inflammation, the number, distribution, and differentiation of goblet cells, ER stress, and apoptosis were measured. We found a biphasic reduction in goblet cell numbers 24 h–2 d after, and 15 d after IA LPS exposure. The second decrease of goblet cell numbers was preceded by intestinal inflammation, apoptosis, and crypt ER stress, and increased SAM-pointed domain-containing ETS transcription factor (SPDEF)-positive cell counts. Our combined findings indicated that ER stress drives apoptosis of maturating goblet cells during chorioamnionitis, ultimately reducing goblet cell numbers. As similar changes have been described in patients suffering from NEC, these findings are considered to be clinically important for understanding the predecessors of NEC, and targeting ER stress in this context is interesting for future therapeutics.

10 THE ROLE OF DIETARY L-SERINE IN THE REGULATION OF INTESTINAL MUCUS BARRIER DURING INFLAMMATION

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S42-S42
Author(s):  
Kohei Sugihara ◽  
Nobuhiko Kamada
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Gut Microbiota ◽  
Control Diet ◽  
Bacterial Strains ◽  
Germ Free ◽  
Intestinal Mucus ◽  
Gnotobiotic Mice ◽  
Mucus Barrier

Abstract Background Recent accumulating evidence suggests that amino acids have crucial roles in the maintenance of intestinal homeostasis. In inflammatory bowel disease (IBD), amino acid metabolism is changed in both host and the gut microbiota. Among amino acids, L-serine plays a central role in several metabolic processes that are essential for the growth and survival of both mammalian and bacterial cells. However, the role of L-serine in intestinal homeostasis and IBD remains incompletely understood. In this study, we investigated the effect of dietary L-serine on intestinal inflammation in a murine model of colitis. Methods Specific pathogen-free (SPF) mice were fed either a control diet (amino acid-based diet) or an L-serine-deficient diet (SDD). Colitis was induced by the treatment of dextran sodium sulfate (DSS). The gut microbiome was analyzed by 16S rRNA sequencing. We also evaluate the effect of dietary L-serine in germ-free mice and gnotobiotic mice that were colonized by a consortium of non-mucolytic bacterial strains or the consortium plus mucolytic bacterial strains. Results We found that the SDD exacerbated experimental colitis in SPF mice. However, the severity of colitis in SDD-fed mice was comparable to control diet-fed mice in germ-free condition, suggesting that the gut microbiota is required for exacerbation of colitis caused by the restriction of dietary L-serine. The gut microbiome analysis revealed that dietary L-serine restriction fosters the blooms of a mucus-degrading bacterium Akkermansia muciniphila and adherent-invasive Escherichia coli in the inflamed gut. Consistent with the expansion of mucolytic bacteria, SDD-fed mice showed a loss of the intestinal mucus layer. Dysfunction of the mucus barrier resulted in increased intestinal permeability, thereby leading to bacterial translocation to the intestinal mucosa, which subsequently increased the severity of colitis. The increased intestinal permeability and subsequent bacterial translocation were observed in SDD-fed gnotobiotic mice that colonized by mucolytic bacteria. In contrast, dietary L-serine restriction did not alter intestinal barrier integrity in gnotobiotic mice that colonized only by non-mucolytic bacteria. Conclusion Our results suggest that dietary L-serine regulates the integrity of the intestinal mucus barrier during inflammation by limiting the expansion of mucus degrading bacteria.

scholarly journals Does the possession of virulence factor genes mean that those genes will be active?

2009 ◽  
Vol 7 (S1) ◽  
pp. S19-S28 ◽  
Author(s):  
Stephen C. Edberg
Keyword(s):  
Public Health ◽  
Gastrointestinal Tract ◽  
Virulence Factors ◽  
Alimentary Tract ◽  
The Body ◽  
Normal Flora ◽  
Mucosal Surfaces ◽  
Stomach Acid ◽  
Specific Receptors ◽  
Virulence Factor Genes

There are a number of relationships the host can establish with the microbes we ingest. For the vast majority of microbes, they have a short-lived liaison with the human host. Either they are destroyed by the stomach acid or bile, or can not establish even a temporary residency in the gastrointestinal tract. Early in life the mucosal surfaces of the body establishes a resident, and generally stable, normal flora. These normal flora microbes, the majority of which are bacteria, have specific receptors for specific areas of the alimentary tract. If the foreign microbe can establish residency, it then may transiently or permanently become part of the normal flora. However, in order to produce disease, it must possess an additional set of virulence factors. While some of these are known, many are not. Those that are known include enzymes, such as protease, lipase, and esterase. Accordingly, VFAR may not be associated with human disease and its presence or absence has no public health meaning.

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

2013 ◽  
Vol 38 (2) ◽  
pp. 135-143 ◽  
Author(s):  
Yuki Ishiwata-Kimata ◽  
Yo-hei Yamamoto ◽  
Ken Takizawa ◽  
Kenji Kohno ◽  
Yukio Kimata
Keyword(s):  
Er Stress ◽  
Type Ii ◽  
Stress Sensor ◽  
Type Ii Myosin

scholarly journals An evolutionarily conserved program of B-cell development and activation in zebrafish

Blood ◽  
2013 ◽  
Vol 122 (8) ◽  
pp. e1-e11 ◽  
Author(s):  
Dawne M. Page ◽  
Valerie Wittamer ◽  
Julien Y. Bertrand ◽  
Kanako L. Lewis ◽  
David N. Pratt ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Transition Point ◽  
Cell Development ◽  
B Cell Development ◽  
Key Points ◽  
Evolutionarily Conserved

Key Points B cells appear in zebrafish by 3 weeks of development, supporting previous data that this is the transition point to adult hematopoiesis. Shifting sites of B-cell development likely occur in all jawed vertebrates.

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