Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis

Kakiuchi, Nobuyuki; Yoshida, Kenichi; Uchino, Motoi; Kihara, Takako; Akaki, Kotaro; Inoue, Yoshikage; Kawada, Kenji; Nagayama, Satoshi; Yokoyama, Akira; Yamamoto, Shuji; Matsuura, Minoru; Horimatsu, Takahiro; Hirano, Toshio; Goto, Norihiro; Takeuchi, Yasuhide; Ochi, Yotaro; Shiozawa, Yusuke; Kogure, Yasunori; Watatani, Yosaku; Fujii, Yoichi; Kim, Soo Ki; Kon, Ayana; Kataoka, Keisuke; Yoshizato, Tetsuichi; Nakagawa, Masahiro; Yoda, Akinori; Nanya, Yasuhito; Makishima, Hideki; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Sanada, Masashi; Sugihara, Eiji; Sato, Taka Aki; Maruyama, Takashi; Miyoshi, Hiroyuki; Taketo, Makoto Mark; Oishi, Jun; Inagaki, Ryosaku; Ueda, Yutaka; Okamoto, Shinya; Okajima, Hideaki; Sakai, Yoshiharu; Sakurai, Takaki; Haga, Hironori; Hirota, Seiichi; Ikeuchi, Hiroki; Nakase, Hiroshi; Marusawa, Hiroyuki; Chiba, Tsutomu; Takeuchi, Osamu; Miyano, Satoru; Seno, Hiroshi; Ogawa, Seishi

doi:10.1038/s41586-019-1856-1

Cited by 197 publications

(155 citation statements)

References 40 publications

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“…This study also suggests that skin inflammation such as that induced by mut-CARD14 may promote BIR. Recent studies on patients with ulcerative colitis have revealed that human intestinal stem cells exposed to long-standing inflammation adapt to such inflammation by acquiring genetic and genomic alterations including LOH, associated with the downregulation of IL-17 signalling 11,12 . Furthermore, long-tract LOH is frequently seen in skin lesions of porokeratosis, a common autoinflammatory keratinisation disease 41 .…”

Section: Discussionmentioning

confidence: 99%

Curing genetic skin disease through altered replication stress response

Miyauchi¹,

Suzuki²,

Takeda³

et al. 2020

Preprint

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Revertant mosaicism, or "natural gene therapy", refers to the spontaneous in vivo reversion of an inherited mutation in a somatic cell. Only ~50 human genetic disorders exhibit revertant mosaicism, implicating a distinctive role played by mutant proteins in somatic correction of a pathogenic germline mutation. However, the process by which mutant proteins induce somatic genetic reversion in these diseases remains unknown. Here we show that heterozygous pathogenic CARD14 mutations causing autoinflammatory skin diseases, including psoriasis and pityriasis rubra pilaris, are repaired mainly via homologous recombination. Rather than altering the DNA damage response to exogenous stimuli such as X-irradiation or etoposide treatment, mutant CARD14 increased DNA double-strand breaks under conditions of replication stress. Furthermore, mutant CARD14 suppressed new origin firings without promoting crossover events in the replication stress state. Together, these results suggest that mutant CARD14 alters the replication stress response and preferentially drives break-induced replication (BIR), which is generally suppressed in eukaryotes. Our results highlight the involvement of BIR in reversion events, thus revealing a previously undescribed role of BIR that could potentially be exploited to develop therapeutics for currently intractable genetic diseases.

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Section: Discussionmentioning

confidence: 99%

Curing genetic skin disease through altered replication stress response

Miyauchi¹,

Suzuki²,

Takeda³

et al. 2020

Preprint

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“… 95 – 98 For example, despite the fact that NF-κB signaling pathway mutations are significantly enriched throughout the colon in patients with ulcerative colitis, these pathways are exceedingly rare in areas of the colon with dysplasia or colitis-associated cancer. 99 A recent study comparing epithelial organoids derived from 71 patients, 16 without colitis, 29 with colitis lacking dysplasia, and 26 from patients with colitis-associated cancer, showed mutations in the IL-17 signaling pathway that confer resistance to an IL-17A-induced apoptotic response. 100 Like novel chemotherapeutic testing for cancer, ulcerative colitis and normal colonic organoids can be treated with cytokines and bacterial components to recapitulate the colitis phenotype, and then treated with novel agents to assess suppression of the immune response and regeneration of normal crypts.…”

Section: Methodsmentioning

confidence: 99%

Organoid Models of Colorectal Pathology: Do They Hold the Key to Personalized Medicine? A Systematic Review

DeHaan

Sarvestani

Huang

2020

Diseases of the Colon &Amp; Rectum

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“…In accordance with this idea, Regnase-1 is involved in the remodeling of the epithelial tissue of patients who have ulcerative colitis (UC). An exome sequencing study showed that ZC3H12A mutation in Ser438, which is present within the DSGXXS motif, is highly enriched in the inflamed tissue of UC samples [146,147]. This mutant form of Regnase-1 is resistant to degradation induced by IL-17-mediated IKK activation and indicates that Regnase-1 suppresses chronic inflammation in the UC epithelium.…”

Section: The Role Of Posttranscriptional Regulation In Immune Homeostmentioning

confidence: 99%

RNA Recognition and Immunity—Innate Immune Sensing and Its Posttranscriptional Regulation Mechanisms

Uehata

Takeuchi

2020

Cells

Self Cite

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RNA acts as an immunostimulatory molecule in the innate immune system to activate nucleic acid sensors. It functions as an intermediate, conveying genetic information to control inflammatory responses. A key mechanism for RNA sensing is discriminating self from non-self nucleic acids to initiate antiviral responses reliably, including the expression of type I interferon (IFN) and IFN-stimulated genes. Another important aspect of the RNA-mediated inflammatory response is posttranscriptional regulation of gene expression, where RNA-binding proteins (RBPs) have essential roles in various RNA metabolisms, including splicing, nuclear export, modification, and translation and mRNA degradation. Recent evidence suggests that the control of mRNA stability is closely involved in signal transduction and orchestrates immune responses. In this study, we review the current understanding of how RNA is sensed by host RNA sensing machinery and discuss self/non-self-discrimination in innate immunity focusing on mammalian species. Finally, we discuss how posttranscriptional regulation by RBPs shape immune reactions.

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Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis

Cited by 197 publications

References 40 publications

Curing genetic skin disease through altered replication stress response

Curing genetic skin disease through altered replication stress response

Organoid Models of Colorectal Pathology: Do They Hold the Key to Personalized Medicine? A Systematic Review

RNA Recognition and Immunity—Innate Immune Sensing and Its Posttranscriptional Regulation Mechanisms

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