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Hepatic Huwe1 loss protects mice from non-alcoholic fatty liver disease through lipid metabolic rewiring

ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of liver disease worldwide and is estimated to affect nearly a third of the population. Huwe1, also known as ARF-BP1, MULE, and HectH9, is a HECT (homology to E6-APC terminus)-domain E3 ubiquitin ligase originally identified as a binding partner of the tumor suppressor ARF, as well as a direct negative regulator of the tumor suppressor p53. To further elucidate the in vivo role of Huwe1, we generated a liver-specific Huwe1 (Huwe1LKO) knockout mouse model. Surprisingly, liver-specific knockout of Huwe1 protected mice from the development of age-induced hepatic steatosis. To elucidate the mechanism underlying this phenotype, bulk RNAseq analysis was performed on liver tissues from 1-year-old Huwe1LKO and Huwe1WTmice.

ORGANISM(S): Mus musculus

PROVIDER: GSE241875 | GEO | 2023/12/06

REPOSITORIES: GEO

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Hepatic Huwe1 loss protects mice from non-alcoholic fatty liver disease through lipid metabolic rewiring

Project description:Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of liver disease worldwide and is estimated to affect nearly a third of the population. Huwe1, also known as ARF-BP1, MULE, and HectH9, is a HECT (homology to E6-APC terminus)-domain E3 ubiquitin ligase originally identified as a binding partner of the tumor suppressor ARF, as well as a direct negative regulator of the tumor suppressor p53. To further elucidate the in vivo role of Huwe1, we generated a liver-specific Huwe1 (Huwe1LKO) knockout mouse model. Surprisingly, liver-specific knockout of Huwe1 protected mice from the development of age-induced hepatic steatosis. To elucidate the mechanism underlying this phenotype, mass spectrometry analysis was performed on liver tissues from 1-year-old Huwe1LKO and Huwe1WT mice.

2024-01-26 | PXD045279 | Pride

Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase

Project description:Deregulated expression of MYC is a driver of colorectal carcinogenesis, necessitating novel strategies to inhibit MYC function. The ubiquitin ligase HUWE1 (HECTH9, ARFBP1, MULE) associates with both MYC and the MYC-associated protein MIZ1. We show here that HUWE1 is required for growth of colorectal cancer cells in culture and in orthotopic xenograft models. Using high throughput screening, we identify small molecule inhibitors of HUWE1, which inhibit MYC-dependent transactivation in colorectal cancer cells, but not in stem and normal colon epithelial cells. Inhibition of HUWE1 stabilizes MIZ1. MIZ1 globally accumulates on MYC target genes and contributes to repression of MYC-activated target genes upon HUWE1 inhibition. Our data show that transcriptional activation by MYC in colon cancer cells requires the continuous degradation of MIZ1 and identify a novel principle that allows for inhibition of MYC function in tumor cells. MIZ1 and MYC ChIPseq experiments in HUWE1 inhibitor-treated Ls174T cells as well as RNAseq experiments in HUWE1- or MIZ1-depleted Ls174T cells after HUWE1 inhibitor treatment. Sequencing was performed on an Illumina Genome Analyzer IIx.

2014-10-21 | E-GEOD-59223 | biostudies-arrayexpress

Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase

2014-10-21 | GSE59223 | GEO

HAPSTR1 localizes HUWE1 to the nucleus to limit stress signaling pathways

Project description:HUWE1 is a large, enigmatic HECT domain ubiquitin ligase implicated in the degradation of numerous substrates and regulating diverse pathways including DNA repair, apoptosis, and differentiation. However, the mechanism by which HUWE1 acts in a pleiotropic manner to regulate a myriad of substrates is unknown. Recent work has established a physical and genetic interaction between HUWE1 and C16orf72/HAPSTR1, suggesting that HAPSTR1 positively regulates HUWE1 function. Here, we show that HAPSTR1 is both a HUWE1 substrate, and is required to localize HUWE1 to the nucleus. Quantitative proteomics across diverse cell types reveals that HUWE1 substrates are largely context specific. Transcriptomics following HUWE1 or HAPSTR1 loss of function reveals a broad transcriptional stress response. We show that nuclear HUWE1 impacts stress signaling pathways, including p53 and NFkB-mediated signaling, and is required for cell proliferation. Together, these data define a critical role for nuclear HUWE1 function that is dependent on HAPSTR1.

2023-05-14 | PXD041590 | Pride

HAPSTR1 localizes HUWE1 to the nucleus to limit stress signaling pathways

2023-05-14 | PXD041593 | Pride

HAPSTR1 localizes HUWE1 to the nucleus to limit stress signaling pathways

2023-05-14 | PXD041595 | Pride

HAPSTR1 localizes HUWE1 to the nucleus to limit stress signaling pathways

2023-05-14 | PXD041591 | Pride

Huwe1-mediated ubiquitylation of Dvl defines a novel negative feedback loop in the Wnt signaling pathway

Project description:Wnt signaling plays a central role in development, adult tissue homeostasis and cancer. Several steps in the canonical Wnt/b-catenin signaling cascade are regulated by ubiquitylation, a protein modification that influences the stability, subcellular localization or protein-protein interactions of target proteins. To identify novel regulators of the Wnt/b-catenin pathway, we performed RNAi screens in C. elegans and human tissue culture cells and identified the HECT domain containing ubiquitin ligase eel-1/Huwe1 as a negative regulator of Wnt signaling. Huwe1 functions cell autonomously in signal-receiving cells and genetically acts upstream of b-catenin. Mechanistically, Huwe1 binds to and ubiquitylates the cytoplasmic Wnt pathway component Dishevelled (Dvl) in a Wnt3a and CK1e dependent manner. Huwe1 mediated ubiquitylation does not target Dvl for degradation. Instead, we found that Huwe1 decreases Dvl signaling by inhibiting Dvl multimerization. We conclude that Huwe1 is part of an evolutionarily conserved negative feedback loop in the Wnt/b-catenin pathway

2014-05-28 | PXD000781 | Pride

Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase

Project description:HUWE1 was depleted in Ls174T cells with an shRNA and the expression changes relative to a control shRNA were analyzed with microarray. Ls174T cells were treated with two separate HUWE1 inhibitor compounds (BI8622/BI8626) at concentrations of 20 uM and expression profiles relative to DMSO treated control were monitored via microarray. HUWE1-depleted Ls174T cells were treated with BI8622 (20uM) and expression profiles relative to BI8622-treated non-depleted cells were analyzed.

2014-10-22 | E-MTAB-1890 | biostudies-arrayexpress

Mapping of the HUWE1 duplication at Xp11.22 in eight unrelated XLID patients

Project description:In a study to elucidate the genetic defects in patients with X-linked intellectual disability (XLID) we performed X chromosome-specific BAC-array-CGH and identified 0.33 to 1.0 Mb nonrecurrent copy number gains at Xp11.22 in affected males of unrelated XLID families. All aberrations segregate with the disease in the families and the carrier mothers show a nonrandom X-inactivation. Affected males suffered from mild to moderate ID. Tiling Xp11.22 region-specific oligo-array (ChrX:52.50 - 54.50 Mb) revealed that all aberrations had different start and stop sites. The twofold copy number gain included up to 20 genes but only the HUWE1 gene is located in the minimal common region of overlap in these families. Moreover, expression analysis revealed about twofold increased HUWE1 mRNA levels in affected patients when compared to control individuals. Breakpoint analysis revealed Non-homologous end-joining (4 cases), serial replication slippage (1 case) and non-allelic homologous recmbination (one case) as the potential recombination mechanism. For duplication mapping and exact copy number analysis in all four families, differentially-labeled patient versus male control DNA samples were hybridized onto a custom designed 4x44k oligo-array (Agilent Technologies) that covers the repeat-masked region 52.50 Mb to 54.50 Mb at tiling resolution.

2012-09-03 | E-GEOD-32945 | biostudies-arrayexpress

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