Yip1 domain family, member 6 (Yipf6) mutation induces spontaneous intestinal inflammation in mice

Brandl, Katharina; Tomisato, Wataru; Li, Xiaohong; Neppl, Christina; Pirie, Elaine; Falk, Werner; Xia, Yu; Moresco, Eva Marie Y.; Baccalà, Roberto; Theofilopoulos, Argyrios N.; Schnabl, Bernd; Beutler, Bruce

doi:10.1073/pnas.1210366109

Cited by 27 publications

(29 citation statements)

References 21 publications

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“…Gene amplification of YIPF6 has been previously reported in CRPC, but the functional importance of this was not clarified . We found YIPF6 protein expression in the Golgi of PC cells, in line with what has been reported earlier for YIP1 family members and, importantly, overexpression of YIPF6 in 22Rv1 PC cells resulted in enhanced secretion of EVs. The 22Rv1 cells secreted two subclasses of EVs, based on size, and YIPF6 overexpression obviously resulted in increased secretion of the smaller subclass, including EVs with a size (83 nm) similar to what is repeatedly reported for exosomes .…”

Section: Discussionsupporting

confidence: 88%

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High levels of the AR-V7 Splice Variant and Co-Amplification of the Golgi Protein CodingYIPF6inARAmplified Prostate Cancer Bone Metastases

et al. 2017

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AR amplified CRPC bone metastases show high AR-V7 expression that probably gives resistance to AR-targeting drugs. Co-amplification of the Golgi protein coding YIPF6 gene with the AR may enhance the secretion of pro-coagulative EVs from cancer cells and thereby stimulate tumor progression and increase the coagulopathy risk in CRPC patients. Prostate 77: 625-638, 2017. © 2017 Wiley Periodicals, Inc.

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Section: Discussionsupporting

confidence: 88%

“…In line with the reported role of YIP family proteins in yeast, stimulating secretion and intracellular vesicle transport ( [8,9] and reviewed in Ref. [10]) we wanted to investigate if YIPF6 affected the release of EVs from cancer cells.…”

Section: Overexpression Of Yipf6 In 22rv1 Cells Reduces Cell Prolifermentioning

confidence: 99%

High levels of the AR-V7 Splice Variant and Co-Amplification of the Golgi Protein CodingYIPF6inARAmplified Prostate Cancer Bone Metastases

et al. 2017

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“…Moreover, the NAALADL2 -associated rs3914501 risk allele was associated with poor prognosis of intestinal BD. Dysfunction of YIP1 family members may deregulate intestinal homeostasis, leading to a pathogenic state23. Mice with null mutated Yipf6 were extremely sensitive to dextran sodium sulfate (DSS)-induced colitis.…”

Section: Discussionmentioning

confidence: 99%

Identification of genetic susceptibility loci for intestinal Behçet’s disease

Kim

Jung

Ahn

et al. 2017

Sci Rep

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Several recent genome-wide association studies (GWAS) identified susceptibility loci/genes for Behçet’s disease (BD). However, no study has specifically investigated the genetic susceptibility loci associated with intestinal involvement in BD. We aimed to identify distinctive genetic susceptibility loci/genes associated with intestinal involvement in BD and determine their roles in intestinal inflammation as well as their interactions with genes involved in inflammatory bowel disease (IBD). GWAS and validation studies showed intestinal BD-specific associations with an NAALADL2 gene locus (rs3914501, P = 3.8 × 10−4) and a YIPF7 gene locus (rs6838327, P = 3.5 × 10−4). Validation, haplotype, and pathway analyses showed distinct genetic architectures between intestinal BD and BD without intestinal involvement. Furthermore, network analysis revealed shared pathogenic pathways between intestinal BD and IBD. Gene functional analyses indicated that down-regulation of NAALADL2 and YIPF7 expression was associated with exacerbating intestinal inflammatory responses both in vitro and in vivo. Our results provide new insights into intestinal BD-specific genetic variations, which represents a distinct pathway from BD without intestinal involvement. Functional consequences of the intestinal BD-specific NAALADL2 and YIPF7 expression patterns proved a suggestive association with intestinal inflammation risk, which warrants further validation.

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“…Restoration of intestinal homeostasis requires several factors, including epithelial cell proliferation and differentiation, vesicle trafficking, protein secretion, integrity of the unfolded protein response pathways, and immune signaling (4)(5)(6)(7)(8). The essential molecular components required for a physiological response to the damage caused by DSS can be revealed by random germline mutagenesis (4).…”

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confidence: 99%

Creatine maintains intestinal homeostasis and protects against colitis

Turer

McAlpine

Wang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Creatine, a nitrogenous organic acid, replenishes cytoplasmic ATP at the expense of mitochondrial ATP via the phosphocreatine shuttle. Creatine levels are maintained by diet and endogenous synthesis from arginine and glycine. Glycine amidinotransferase (GATM) catalyzes the rate-limiting step of creatine biosynthesis: the transfer of an amidino group from arginine to glycine to form ornithine and guanidinoacetate. We screened 36,530 third-generation germline mutant mice derived from N-ethyl-N-nitrosourea–mutagenized grandsires for intestinal homeostasis abnormalities after oral administration of dextran sodium sulfate (DSS). Among 27 colitis susceptibility phenotypes identified and mapped, one was strongly correlated with a missense mutation in Gatm in a recessive model of inheritance, and causation was confirmed by CRISPR/Cas9 gene targeting. Supplementation of homozygous Gatm mutants with exogenous creatine ameliorated the colitis phenotype. CRISPR/Cas9-targeted (Gatmc/c) mice displayed a normal peripheral immune response and immune cell homeostasis. However, the intestinal epithelium of the Gatmc/c mice displayed increased cell death and decreased proliferation during DSS treatment. In addition, Gatmc/c colonocytes showed increased metabolic stress in response to DSS with higher levels of phospho-AMPK and lower levels of phosphorylation of mammalian target of rapamycin (phospho-mTOR). These findings establish an in vivo requirement for rapid replenishment of cytoplasmic ATP within colonic epithelial cells in the maintenance of the mucosal barrier after injury.

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Yip1 domain family, member 6 (Yipf6) mutation induces spontaneous intestinal inflammation in mice

Cited by 27 publications

References 21 publications

High levels of the AR-V7 Splice Variant and Co-Amplification of the Golgi Protein CodingYIPF6inARAmplified Prostate Cancer Bone Metastases

High levels of the AR-V7 Splice Variant and Co-Amplification of the Golgi Protein CodingYIPF6inARAmplified Prostate Cancer Bone Metastases

Identification of genetic susceptibility loci for intestinal Behçet’s disease

Creatine maintains intestinal homeostasis and protects against colitis

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