Linear ubiquitination prevents lipodystrophy and obesity-associated metabolic syndrome
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PROVIDER: PRJNA1242380 | ENA |
REPOSITORIES: ENA
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Project description:Linear ubiquitination prevents lipodystrophy and obesity-associated metabolic syndrome
| PRJNA1269933 | ENA
Project description:Adipocyte hypertrophy during obesity triggers chronic inflammation, leading to metabolic disorders. However, the role of adipocyte-specific inflammatory signalling in metabolic syndrome remains unclear. The linear ubiquitin chain assembly complex, LUBAC, is an E3-ligase that generates non-degradative linear ubiquitination (Lin-Ub). LUBAC regulates NF-κB/MAPK-driven inflammation and prevents cell death triggered by immune receptors like TNF-receptor-1. Here we show that mice lacking HOIP, LUBAC’s catalytic subunit, in adipocytes (HoipA-KO) display lipodystrophy and heightened susceptibility to obesity-induced metabolic syndrome, particularly Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Mechanistically, loss of HOIP attenuates TNF-induced NF-κB activation and promotes cell death in human adipocytes. Inhibiting caspase-8-mediated cell death is sufficient to prevent lipodystrophy and MASLD in HoipA-KO obese mice. Importantly, HOIP expression in adipose tissue positively correlates with metabolic fitness in obese individuals. Overall, our findings reveal a fundamental developmental role for Lin-Ub in adipocytes by mitigating cell death-driven adipose tissue inflammation and protecting against obesity-related metabolic
2025-08-22 | GSE298555 | GEO
Project description:Adipocyte hypertrophy during obesity triggers chronic inflammation, leading to metabolic disorders. However, the role of adipocyte-specific inflammatory signalling in metabolic syndrome remains unclear. The linear ubiquitin chain assembly complex, LUBAC, is an E3-ligase that generates non-degradative linear ubiquitination (Lin-Ub). LUBAC regulates NF-κB/MAPK-driven inflammation and prevents cell death triggered by immune receptors like TNF-receptor-1. Here we show that mice lacking HOIP, LUBAC’s catalytic subunit, in adipocytes (HoipA-KO) display lipodystrophy and heightened susceptibility to obesity-induced metabolic syndrome, particularly Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Mechanistically, loss of HOIP attenuates TNF-induced NF-κB activation and promotes cell death in human adipocytes. Inhibiting caspase-8-mediated cell death is sufficient to prevent lipodystrophy and MASLD in HoipA-KO obese mice. Importantly, HOIP expression in adipose tissue positively correlates with metabolic fitness in obese individuals. Overall, our findings reveal a critical role for Lin-Ub in protecting against obesity-related metabolic syndrome by mitigating cell death-driven adipose tissue inflammation
2025-09-03 | GSE293034 | GEO
Project description:Psoriasis is a chronic inflammatory skin disorder driven by dysregulated immune signaling and keratinocyte activation. While the importance of proinflammatory cytokines such as TNF-α, IL-23, and IL-17 in psoriasis is well established, the upstream mechanisms amplifying these pathways, particularly within keratinocytes, remain incompletely defined. Here, we investigate the role of linear ubiquitination—a post-translational modification catalyzed by the linear ubiquitin chain assembly complex (LUBAC)—in psoriasis pathogenesis using a transgenic mouse model (HOIL-1LΔRING1) with enhanced LUBAC activity. In the imiquimod-induced psoriasis model, HOIL-1LΔRING1 mice exhibited exacerbated skin inflammation characterized by increased epidermal thickness, leukocyte infiltration, and elevated expression of Tnf and Il23a. Transcriptomic and pharmacologic analyses showed that linear ubiquitination amplified TNF-α/NF-κB signaling, and TNF-α blockade ameliorated disease severity. BM chimera experiments demonstrated that this effect was mediated by radio-resistant skin cells, particularly keratinocytes. Flow cytometry and in vitro assays confirmed that keratinocyte-intrinsic linear ubiquitination promotes TNF-α production, which was suppressed by a LUBAC inhibitor. Finally, analyses of human psoriatic skin confirmed elevated linear ubiquitination and LUBAC component expression in keratinocytes. These findings identify linear ubiquitination in keratinocytes as a key amplifier of psoriatic inflammation and a potential therapeutic target.
2025-12-31 | GSE305677 | GEO
Project description:Psoriasis is a chronic inflammatory skin disorder driven by dysregulated immune signaling and keratinocyte activation. While the importance of proinflammatory cytokines such as TNF-α, IL-23, and IL-17 in psoriasis is well established, the upstream mechanisms amplifying these pathways, particularly within keratinocytes, remain incompletely defined. Here, we investigate the role of linear ubiquitination—a post-translational modification catalyzed by the linear ubiquitin chain assembly complex (LUBAC)—in psoriasis pathogenesis using a transgenic mouse model (HOIL-1LΔRING1) with enhanced LUBAC activity. In the imiquimod-induced psoriasis model, HOIL-1LΔRING1 mice exhibited exacerbated skin inflammation characterized by increased epidermal thickness, leukocyte infiltration, and elevated expression of Tnf and Il23a. Transcriptomic and pharmacologic analyses showed that linear ubiquitination amplified TNF-α/NF-κB signaling, and TNF-α blockade ameliorated disease severity. BM chimera experiments demonstrated that this effect was mediated by radio-resistant skin cells, particularly keratinocytes. Flow cytometry and in vitro assays confirmed that keratinocyte-intrinsic linear ubiquitination promotes TNF-α production, which was suppressed by a LUBAC inhibitor. Finally, analyses of human psoriatic skin confirmed elevated linear ubiquitination and LUBAC component expression in keratinocytes. These findings identify linear ubiquitination in keratinocytes as a key amplifier of psoriatic inflammation and a potential therapeutic target.
2025-12-31 | GSE305680 | GEO
Project description:A-to-I RNA editing prevents an inflammation-mediated lipodystrophy in adipose tissue
| PRJNA1173569 | ENA
Project description:Ubiquitination of hepatic APOC3 by GM47544 prevents hypertriglyceridemia and ameliorates atherosclerosis
| PRJNA974253 | ENA
Project description:While linear ubiquitin plays critical roles in multiple cell signaling pathways, few substrates have been identified. Global profiling of linear ubiquitin substrates represents a significant challenge because of the low endogenous level of linear ubiquitination, the none-specific binding of linear polyubiquitin chain, and the high background interferences arising from heterogeneous ubiquitin linkages (e.g. K48-, K63-). We developed a bioorthogonal linear ubiquitin probe by site-specific encoding of a norbornene amino acid (NAEK) on ubiquitin. This probe facilitates covalent labeling of linear ubiquitin substrates in live cells and enables selective enrichment and identification of linear-ubiquitin modified proteins. we applied this probe in the profiling of substrates of linear ubiquitination in HEK293T cells and GSCs.
2022-02-11 | PXD031600 |
Project description:Linear Ubiquitination in Keratinocytes Amplifies Psoriatic inflammation via TNF-α/NF-κB Signaling [RNA-seq]
| PRJNA1307459 | ENA
Project description:Hypoxia is the most prominent feature in human solid tumors and induces activation of hypoxia-inducible factors and their downstream genes to promote cancer progression. However, whether and how hypoxia regulates overall mRNA homeostasis is unclear. Here we show that hypoxia inhibits global-mRNA decay in cancer cells. Mechanistically, hypoxia induces the interaction of AGO2 with HOIL-1L/HOIP, two crucial components of a linear ubiquitin chain assembly complex, which co-localizes with miRNA-induced silencing complex and in turn catalyzes AGO2 occurring Met1-linked linear ubiquitination (M1-Ubi). A series of biochemical experiments reveal that M1-Ubi of AGO2 restrains miRNA-mediated gene silencing. Moreover, combination analyses of the AGO2-associated mRNA transcriptome by RIP-Seq and the mRNA transcriptome by RNA-Seq confirm that AGO2 M1-Ubi interferes miRNA-targeted mRNA recruiting to AGO2, and thereby facilitates accumulation of global mRNAs. By this mechanism, short-term hypoxia may protect overall mRNAs and enhances stress tolerance, whereas long-term hypoxia in tumor cells results in serious changing the entire gene expression profile, which is a driving force in the dynamic process of cell malignant evolution.
2020-09-26 | GSE158601 | GEO