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Telomere dysfunction activates YAP1 to drive tissue inflammation

ABSTRACT: Inflammatory bowel disease (IBD) is a challenging condition with limited therapeutic options. Inflammasome activation is integral to IBD pathogenesis, although the molecular instigators of its activation remain obscure. Here, we establish that telomere dysfunction activates the Yap1 transcriptional co-activator through pATM/c-Abl, which up-regulates expression of microbial receptors Nlrc4 and Nlrc5 and the cytokine pre-IL-18. Microbial engagement of these cytosolic receptors leads to production of mature IL-18, recruiting T cells and other immunocytes which secrete IFN-gamma to drive classical IBD pathology. Genotoxic stress per se (ionizing radiation) can also drive inflammasome activation. Alleviation of IBD pathology can be achieved via telomerase reactivation in intestinal epithelium, antibiotic treatment or pharmacological inhibition of Yap1 - reducing Nlrc4/5 expression as well as IL-18 and IFN-gamma production. Thus, telomere dysfunction-induced inflammasome activation identifies DNA damage signaling as a key instigator and promoter of IBD, illuminating potential novel therapeutic strategies for prevention and disease management.

ORGANISM(S): Mus musculus

PROVIDER: GSE108902 | GEO | 2020/01/01

REPOSITORIES: GEO

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Telomere dysfunction instigates inflammation in inflammatory bowel disease

Project description:Abstract: Inflammatory bowel disease (IBD) is a chronic inflammatory condition driven by diverse genetic and nongenetic programs that converge to disrupt immune homeostasis in the intestine. We have reported that, in murine intestinal epithelium with telomere dysfunction, DNA damage-induced activation of ataxia-telangiectasia mutated (ATM) results in ATM-mediated phosphorylation and activation of the YAP1 transcriptional coactivator, which in turn up-regulates pro-IL-18, a pivotal immune regulator in IBD pathogenesis. Moreover, individuals with germline defects in telomere maintenance genes experience increased occurrence of intestinal inflammation and show activation of the ATM/YAP1/pro-IL-18 pathway in the intestinal epithelium. Here, we sought to determine the relevance of the ATM/YAP1/pro-IL-18 pathway as a potential driver of IBD, particularly older-onset IBD. Analysis of intestinal biopsy specimens and organoids from older-onset IBD patients documented the presence of telomere dysfunction and activation of the ATM/YAP1/ precursor of interleukin 18 (pro-IL-18) pathway in the intestinal epithelium. Employing intestinal organoids from healthy individuals, we demonstrated that experimental induction of telomere dysfunction activates this inflammatory pathway.

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An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome

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SINE RNAs trigger noncanonical NLRC4 inflammasome via DDX17

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TNFR2 induced priming of the inflammasome leads to a RIPK1-dependent cell death in the absence of XIAP

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2021-03-01 | E-MTAB-10103 | biostudies-arrayexpress

Telomere dysfucntion activates YAP1 to drive tissue inflammation [ChIP-seq]

Project description:Germline telomere maintenance defects provoke inflammatory disease via activated ATM/YAP1/IL-18 signaling in epithelial cells, providing novel therapies for inflammatory conditions associated with short telomeres.

2020-02-29 | GSE144200 | GEO

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2012-01-01 | E-GEOD-34492 | biostudies-arrayexpress

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