ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells

Niederreiter, Lukas; Fritz, T; Adolph, Timon E.; Krismer, Anna-Maria; Offner, Felix; Tschurtschenthaler, Markus; Flak, Magdalena B.; Hosomi, Shuhei; Tomczak, Michal; Kaneider, Nicole C.; Sarcevic, Edina; Kempster, Sarah; Raine, Tim; Esser, Daniela; Rosenstiel, Philip; Kohno, Kenji; Tilg, Herbert; Blumberg, Richard S.; Kaser, Arthur

doi:10.1083/jcb.2027oia100

Cited by 26 publications

(36 citation statements)

References 77 publications

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“…In accordance with our findings that IRE1a is linked to enhancement of STAT3 activation in hepatocyte proliferation, Niederreiter et al reported increased STAT3 phosphorylation during the regenerative response in the intestinal epithelium, in association with higher expression and hyperactivation of IRE1a, resulting from XBP1 deletion in mice [45]. However, they did not observe reduced STAT3 activation in the XBP1;IRE1a double knockout mouse model.…”

Section: Discussionsupporting

confidence: 91%

Role for the endoplasmic reticulum stress sensor IRE1α in liver regenerative responses

Shao

Cheng

et al. 2015

Journal of Hepatology

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Section: Discussionsupporting

confidence: 91%

Role for the endoplasmic reticulum stress sensor IRE1α in liver regenerative responses

Shao

Cheng

et al. 2015

Journal of Hepatology

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“…It has been proposed that the IRE1-XBP1 axis is involved in the differentiation of many cell types that possess high secretory capacity through the activation of ER expansion programs. 14,27 For instance, UPR-mediated XBP1 production and splicing has been implicated in Bcell to plasma cell differentiation, 7 the differentiation of eosinophils 5 as well as proper production of mucin from goblet cells. 28 Furthermore, IL-4 is one of the main Th2 cytokines that drives B cell differentiation into antibodysecreting plasma cells via an XBP1 dependent mechanism.…”

Section: Discussionmentioning

confidence: 99%

IL‐6 mediates ER expansion during hyperpolarization of alternatively activated macrophages

et al. 2018

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Although recent evidence has shown that IL‐6 is involved in enhanced alternative activation of macrophages toward a profibrotic phenotype, the mechanisms leading to their increased secretory capacity are not fully understood. Here, we investigated the effect of IL‐6 on endoplasmic reticulum (ER) expansion and alternative activation of macrophages in vitro. An essential mediator in this ER expansion process is the IRE1 pathway, which possesses a kinase and endoribonuclease domain to cleave XBP1 into a spliced bioactive molecule. To investigate the IRE1‐XBP1 expansion pathway, IL‐4/IL‐13 and IL‐4/IL‐13/IL‐6‐mediated alternative programming of murine bone marrow‐derived and human THP1 macrophages were assessed by arginase activity in cell lysates, CD206 and arginase‐1 expression by flow cytometry, and secreted CCL18 by ELISA, respectively. Ultrastructural intracellular morphology and ER biogenesis were examined by transmission electron microscopy and immunofluorescence. Transcription profiling of 128 genes were assessed by NanoString and Pharmacological inhibition of the IRE1‐XBP1 arm was achieved using STF‐083010 and was verified by RT‐PCR. The addition of IL‐6 to the conventional alternative programming cocktail IL‐4/IL‐13 resulted in increased ER and mitochondrial expansion, profibrotic profiles and unfolded protein response‐mediated induction of molecular chaperones. IRE1‐XBP1 inhibition substantially reduced the IL‐6‐mediated hyperpolarization and normalized the above effects. In conclusion, the addition of IL‐6 enhances ER expansion and the profibrotic capacity of IL‐4/IL‐13‐mediated activation of macrophages. Therapeutic strategies targeting IL‐6 or the IRE1‐XBP1 axis may be beneficial to prevent the profibrotic capacity of macrophages.

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“…Xbp1s mRNA encodes the transcription factor XBP1s, which induces an array of genes involved in the recovery of ER functions (8,9). The IRE1α/XBP1 pathway is the most evolutionarily conserved branch of the UPR (4); however, past studies revealed that this pathway also possesses functions that are not directly related to the UPR, including the regulation of innate immunity, energy metabolism, and cell differentiation (8,(10)(11)(12)(13)(14)(15). These observations suggest that the IRE1α/XBP1 pathway is a critical component that integrates the UPR with the regulation of various cell-fate decisions.…”

Section: Introductionmentioning

confidence: 99%

IRE1α/XBP1-mediated branch of the unfolded protein response regulates osteoclastogenesis

Tohmonda¹,

Yoda²,

Iwawaki³

et al. 2015

J. Clin. Invest.

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(T. Tohmonda).lowed by Alexa Fluor 488-conjugated anti-rabbit IgG (Invitrogen); nuclei were counterstained with DAPI. Images of the cells were acquired with Olympus DP controller software via an Olympus DP70 camera mounted on an Olympus IX71 microscope at room temperature. The objective was a ×100 APO/1.65 NA lens. Images were processed with Adobe Photoshop CS6 for contrast correction and to generate merged images.Statistics. All statistical analyses were performed using Prism 6 (GraphPad Software). Two-tailed Student's t tests for 2 samples assuming equal variances were used to calculate the P values. P < 0.05 was considered significant.Study approval. All of the animal experiments in this study were approved by the Institutional Animal Care and Use Committee of the

show abstract

ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells

Cited by 26 publications

References 77 publications

Role for the endoplasmic reticulum stress sensor IRE1α in liver regenerative responses

Role for the endoplasmic reticulum stress sensor IRE1α in liver regenerative responses

IL‐6 mediates ER expansion during hyperpolarization of alternatively activated macrophages

IRE1α/XBP1-mediated branch of the unfolded protein response regulates osteoclastogenesis

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