Identification of Ubr1 as an amino acid sensor of steatosis in liver and muscle

Zhao, Wanni; Zhang, Yansong; Lin, Siyuan; Li, Yajuan; Zhu, Alan Jian; Shi, Hanping; Liu, Min

doi:10.1002/jcsm.13233

Cited by 7 publications

(3 citation statements)

References 40 publications

(103 reference statements)

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Section: Perilipinmentioning

confidence: 99%

“…The ubiquitin-proteasome pathway consistently degrades expressed PLIN2, a process that involves the E3 ubiquitin ligase (Ubr1) [70,71]. Ubr1 targets PLIN2 for degradation in an amino acid-dependent manner [71]. This increase in Ubr1 activity results in enhanced ubiquitination of PLIN2, which facilitates the access of lipolytic enzymes to the LD core.…”

Section: Perilipinmentioning

confidence: 99%

See 1 more Smart Citation

Challenges in Pharmacological Intervention in Perilipins (PLINs) to Modulate Lipid Droplet Dynamics in Obesity and Cancer

Bombarda-Rocha,

Silva,

Badr-Eddine

et al. 2023

Cancers

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Perilipins (PLINs) are the most abundant proteins in lipid droplets (LD). These LD-associated proteins are responsible for upgrading LD from inert lipid storage structures to fully functional organelles, fundamentally integrated in the lipid metabolism. There are five distinct perilipins (PLIN1–5), each with specific expression patterns and metabolic activation, but all capable of regulating the activity of lipases on LD. This plurality creates a complex orchestrated mechanism that is directly related to the healthy balance between lipogenesis and lipolysis. Given the essential role of PLINs in the modulation of the lipid metabolism, these proteins can become interesting targets for the treatment of lipid-associated diseases. Since reprogrammed lipid metabolism is a recognized cancer hallmark, and obesity is a known risk factor for cancer and other comorbidities, the modulation of PLINs could either improve existing treatments or create new opportunities for the treatment of these diseases. Even though PLINs have not been, so far, directly considered for pharmacological interventions, there are many established drugs that can modulate PLINs activity. Therefore, the aim of this study is to assess the involvement of PLINs in diseases related to lipid metabolism dysregulation and whether PLINs can be viewed as potential therapeutic targets for cancer and obesity.

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Section: Perilipinmentioning

confidence: 99%

Section: Perilipinmentioning

confidence: 99%

Challenges in Pharmacological Intervention in Perilipins (PLINs) to Modulate Lipid Droplet Dynamics in Obesity and Cancer

Bombarda-Rocha,

Silva,

Badr-Eddine

et al. 2023

Cancers

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“…The human genome encodes over 600 E3 enzymes, some of which are crucial targets for various drug therapies. UBR1 is linked to various human diseases, including steatosis [13,14] , pancreatic dysfunction, malformation, Johnson-Blizzard syndrome (JBS) [15] and cancer. However, the function and regulatory mechanisms of UBR1 in GC have not yet been documented.…”

Section: Introductionmentioning

confidence: 99%

UBR1 is a prognostic biomarker and therapeutic target associated with immune cell infiltration in gastric cancer

Wang¹,

Han²,

Wu³

et al. 2023

Preprint

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Background Ubiquitination is a targeted protein modification process mediated by intracellular molecules. UBR1 encodes a protein that binds to unstable N-terminal residues of substrate proteins and contributes to the formation of substrate-linked polyubiquitin chains. However, the cellular pathways and the function of UBR1 in tumors have received inadequate attention. Therefore, the aim of this study is to examine the potential of UBR1 as a prognostic biomarker and immunotherapy target for stomach adenocarcinoma (STAD) as well as its biological function and molecular mechanism in relation to the disease. Methods Differential expression and pan-cancer GSEA analyses were performed using TCGA, GEO and GTEx datasets. Immunohistochemical differences between cancer and paraneoplastic tissues were analyzed using the HPA database to identify pathways enriched by UBR1 in AGS cells. Besides, with the help of Kaplan-Meier curves, univariate and multivariate Cox regression, and receiver operating characteristic (ROC) curve studies, the prognostic and diagnostic roles of UBR1 can be identified and determined. The correlation between UBR1 expression and clinical parameters was predicted by using the TCGA and GEO databases. The UBR1 mutation data were retrieved from the cBioPortal database. The biological mechanisms of UBR1 were investigated using GO and KEGG enrichment analyses. TIMER and EPIC computational methods were utilized to establish the connection between UBR1 and immune infiltration. Protein expression was determined using immunohistochemistry (IHC) and Western blot analysis (WB). In regard to mRNA expression, Quantitative Real-time PCR (qRT-PCR), it was analyzed by taking advantage of Quantitative Real-time PCR (qRT-PCR). Quantitative Immunoprecipitation (IP) assays were used to detect protein-protein interactions. Cell proliferation was evaluated using CCK8 and colony formation assays. Cell invasion was determined using wound healing assays and Transwell. Apoptosis was analyzed using flow cytometry. Result UBR1 was upregulated in 28 cancer types,including STAD, and its overexpression was validated in gastric cancer cell lines and tissues. UBR1 expression was associated with advanced pathological characteristics. High UBR1 expression was linked to poor prognostic outcomes, including progression-free interval (PFI), overall survival (OS), disease-specific survival (DSS), surgery, chemotherapy, and HER2 expression. UBR1 expression was significantly correlated with clinical parameters, such as age, gender, TMN stage, pathological stage, tumor resection, and anti-reflux therapy. Amplifications and deletions were the frequent genetic alterations associated with UBR1. According to the KEGG and GSEA, UBR1 was significantly associated with several cancer pathways, oxidative phosphorylation, and the TNF-NFκB pathway. UBR1 exhibited a significant correlation with immunotherapy and immune cell infiltration, and a direct interaction with CD274. Also, the proliferation and invasion of STAD cells were inhibited due to the UBR1 knockdown, but apoptosis was promoted in a contrary way. Conclusion The results of this investigation show that UBR1 is overexpressed in STAD, promoting its progression, and positively correlates with immune cell infiltration and immunotherapeutic responses. Therefore, UBR1 could be a promising biomarker in the prognosis and immunotherapy field of STAD.

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Identification of Ubr1 as an amino acid sensor of steatosis in liver and muscle

Zhao

Zhang

Lin

et al. 2023

J cachexia sarcopenia muscle

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Background Malnutrition is implicated in human metabolic disorders, including hepatic steatosis and myosteatosis. The corresponding nutrient signals and sensors as well as signalling pathways have not yet been well studied. This study aimed to unravel the nutrient-sensing mechanisms in the pathogenesis of steatosis. Methods Plin2, a lipid droplet (LD) protein-inhibiting lipolysis, is associated with steatosis in liver and muscle. Taking advantage of the Gal4-UAS system, we used the Drosophila melanogaster wing imaginal disc as an in vivo model to study the regulation of Plin2 proteostasis and LD homeostasis. Drosophila Schneider 2 (S2) cells were used for western blotting, immunoprecipitation assays, amino acid-binding assays and ubiquitination assays to further investigate the regulatory mechanisms of Plin2 in response to nutrient signals. Mouse AML12 hepatocytes, human JHH-7 and SNU-475 hepatoma cells were used for immunofluorescence, western blotting and immunoprecipitation to demonstrate that the mode of Plin2 regulation is evolutionarily conserved. In addition, we purified proteins from HEK293 cells and reconstituted in vitro cell-free systems in amino acid-binding assays, pulldown assays and ubiquitination assays to directly demonstrate the molecular mechanism by which Ubr1 senses amino acids to regulate Plin2 proteostasis. Results As a lipolysis inhibitor, Plin2 was significantly elevated in liver (P < 0.05) and muscle (P < 0.05) in patients with steatosis. Consistently, we found that the ubiquitin moiety can be conjugated to any Lys residue in Plin2, ensuring robust clearance of Plin2 by protein degradation. We further demonstrated that the E3 ubiquitin ligase Ubr1 targets Plin2 for degradation in an amino acid-dependent manner. Ubr1 uses two canonical substrate-binding pockets, independent of each other, to bind basic and bulky hydrophobic amino acids, respectively. Mechanistically, amino acid binding allosterically activates Ubr1 by alleviating Ubr1's auto-inhibition. In the absence of amino acids, or when the amino acid-binding capacity of Ubr1 is diminished, Ubr1-mediated Plin2 degradation is inactivated, leading to steatosis. Conclusions We identified Ubr1 as an amino acid sensor regulating Plin2 proteostasis, bridging the knowledge gap between steatosis and nutrient sensing. Our work may provide new strategies for the prevention and treatment of steatosis.

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Identification of Ubr1 as an amino acid sensor of steatosis in liver and muscle

Cited by 7 publications

References 40 publications

Challenges in Pharmacological Intervention in Perilipins (PLINs) to Modulate Lipid Droplet Dynamics in Obesity and Cancer

Challenges in Pharmacological Intervention in Perilipins (PLINs) to Modulate Lipid Droplet Dynamics in Obesity and Cancer

UBR1 is a prognostic biomarker and therapeutic target associated with immune cell infiltration in gastric cancer

Identification of Ubr1 as an amino acid sensor of steatosis in liver and muscle

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