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Acetylation changes in NQO1 overexpression in Mouse Skeletal Mucscle

ABSTRACT: In this manuscript we have explored the role of both Nrf2 and NQO1 in protection against diet-induced metabolic syndrome and demonstrate that both Nrf2 and NQO1 provide protection against HFD-induced adverse phenotypes in a mouse model

INSTRUMENT(S): 6550A iFunnel Q-TOF LC/MS

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Skeletal Muscle

SUBMITTER: Cole Michel

LAB HEAD: Kristofer Fritz

PROVIDER: PXD015070 | Pride | 2021-09-08

REPOSITORIES: Pride

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NQO1 protects obese mice through improvements in glucose and lipid metabolism.

Di Francesco Andrea A Choi Youngshim Y Bernier Michel M Zhang Yingchun Y Diaz-Ruiz Alberto A Aon Miguel A MA Kalafut Krystle K Ehrlich Margaux R MR Murt Kelsey K Ali Ahmed A Pearson Kevin J KJ Levan Sophie S Preston Joshua D JD Martin-Montalvo Alejandro A Martindale Jennifer L JL Abdelmohsen Kotb K Michel Cole R CR Willmes Diana M DM Henke Christine C Navas Placido P Villalba Jose Manuel JM Siegel David D Gorospe Myriam M Fritz Kristofer K Biswal Shyam S Ross David D de Cabo Rafael R de Cabo Rafael R

NPJ aging and mechanisms of disease 20201119 1

Chronic nutrient excess leads to metabolic disorders and insulin resistance. Activation of stress-responsive pathways via Nrf2 activation contributes to energy metabolism regulation. Here, inducible activation of Nrf2 in mice and transgenesis of the Nrf2 target, NQO1, conferred protection from diet-induced metabolic defects through preservation of glucose homeostasis, insulin sensitivity, and lipid handling with improved physiological outcomes. NQO1-RNA interaction mediated the association with ...[more]

PMID: 33298924

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Quantifying Competition Among Mitochondrial Protein Acylation Events Induced by Ethanol Metabolism

Project description:Mitochondrial dysfunction is one of many key factors in the etiology of alcoholic liver disease (ALD). Lysine acetylation is known to regulate numerous mitochondrial metabolic pathways and recent reports demonstrate that alcohol-induced protein acylation negatively impacts these processes. To identify regulatory mechanisms attributed to alcohol-induced protein post-translational modifications, we employed a model of alcohol consumption within the context of wild type (WT), sirtuin 3 knockout (SIRT3 KO), and sirtuin 5 knockout(SIRT5 KO) mice to manipulate hepatic mitochondrial protein acylation. Mitochondrial fractions were examined by label-free quantitative HPLC-MS/MS to reveal competition between lysine acetylation and succinylation. A class of proteins defined as “differential acyl switching proteins” demonstrate select sensitivity to alcohol-induced protein acylation. A number of these proteins reveal saturated lysine-site occupancy, suggesting a significant level of differential stoichiometry in the setting of ethanol consumption. We hypothesize that ethanol downregulates numerous mitochondrial metabolic pathways through differential acyl switching proteins.

2019-01-23 | PXD012089 | Pride

Aggrelyte-2 Promotes Protein Solubility and Decreases Stiffness in Lenses through Lysine Acetylation and Disulfide Reduction

Project description:Aging proteins in the lens become increasingly aggregated and insoluble, contributing to presbyopia. In this study, we investigated the ability of aggrelyte-2 (N,S-Diacetyl-L-cysteine methyl ester) to reverse the water insolubility of aged human lens proteins and to decrease stiffness in cultured human and rodent lenses. Aggrelyte-2 was incubated (500 µM) with water-insoluble proteins of aged human lenses (65-75 years) for 24 or 48 h. A control compound that lacked an S-acetyl group (aggrelyte-2C) was also tested. We observed 19-30% solubility of WI upon the treatment with aggrelyte-2. Aggrelyte-2C also increased protein solubility, but its effect was approximately 1.4-fold lower than that of aggrelyte-2. The protein thiol contents were 1.9 to 4.9-fold higher in the aggrelyte-treated samples than in the untreated samples. The LC-MS/MS results showed N-acetyllysine (AcK) levels of 1.5 to 2.1 nmoles/mg protein and 0.6 to 0.9 nmoles/mg protein in the aggrelyte-2- and aggrelyte-2C-treated samples, respectively. Mouse (C57BL/6J) lenses (incubated for 24 h) and human lenses (incubated for 72 h) with 1.0 mM aggrelyte-2 showed significant decreases in stiffness with simultaneous increases in soluble proteins (human lenses) and protein-AcK levels and such changes were not observed in aggrelyte-2C treated lenses. Mass spectrometry of the solubilized protein revealed AcK in all crystallins but more in α-crystallins. These results suggest that aggrelyte-2 increases protein solubility and decreases lens stiffness through acetylation and disulfide reduction. Aggrelyte-2 might be useful in treating presbyopia in humans.

2023-05-10 | PXD035049 | Pride

Deacetylation inhibition reverses PABPN1-dependent muscle wasting

Project description:Reduced PABPN1 levels cause aging-associated muscle wasting. PABPN1 is a multi-functional regulator of mRNA processing. To elucidate the molecular mechanisms causing PABPN1-mediated muscle wasting, we compared the transcriptome to the proteome in mouse muscles expressing shRNA to PABPN1 (shPab). We found greater variations in the proteome as compared to mRNA expression profiles. Protein accumulation in the shPab proteome was concomitant with reduced proteasomal activity. Notably, protein acetylation appeared to be enriched in shPab versus control proteomes (63%). An acetylome study in shPab muscles revealed prominent peptide deacetylation associated with elevated sirtuin-1 (SIRT1) deacetylase. We show that SIRT1 mRNA levels are controlled by PABPN1 via an alternative polyadenylation site utilization. SIRT1 inhibition reversed PABPN1 activity and muscle cell function. Moreover, deacetylation inhibition increased PABPN1 levels and reversed muscle wasting. We suggest that perturbation of a multifactorial regulatory loop involving PABPN1 and SIRT1 plays an imperative role in aging-associated muscle wasting.

2022-02-28 | PXD011534 | Pride

Multivalent lipid targeting by the calcium-independent C2A domain of Slp-4/granuphilin

Project description:Synaptotagmin-like protein 4 (Slp-4), also known as granuphilin, is a Rab effector responsible for docking insulin secretory vesicles to the plasma membrane prior to exocytosis. Slp-4 binds vesicular Rab proteins via an N-terminal Slp homology (SHD) domain, interacts with plasma membrane SNARE complex proteins via a central linker region, and contains tandem C-terminal C2 domains (C2A and C2B) with affinity for phosphatidylinositol-(4,5)-bisphosphate (PIP2). Its C2A domain has previously been shown to bind PIP2 or its soluble analogues with low micromolar affinity; however, the domain docks with low nanomolar apparent affinity to PIP2 in lipid vesicles that also contain background anionic lipids such as phosphatidylserine (PS). Here we show using a combination of computational and experimental approaches that this high-affinity membrane interaction arises from concerted interaction at multiple sites on the C2A domain. In addition to the previously identified, PIP2-selective lysine cluster, a larger cationic surface surrounding the cluster contributes substantially to the affinity for physiologically relevant lipid compositions. While mutations at the PIP2-selective site decreases affinity for PIP2, multiple mutations are needed to decrease binding to physiologically relevant lipid compositions. Docking and molecular dynamics simulations indicate several conformationally flexible loops that contribute to the nonspecific cationic surface. In addition, we identify and characterize a covalently modified variant in the bacterially expressed protein, which arises through reactivity of the PIP2-binding lysine cluster with endogenous bacterial compounds and has a low membrane affinity. Overall, multivalent lipid binding by the Slp-4 C2A domain provides selective recognition and high affinity docking of large dense-core secretory vesicles to the plasma membrane.

2020-12-08 | PXD021393 | Pride

SARS-CoV-2 Nsp6 damages Drosophila heart and mouse cardiomyocytes through MGA/MAX complex-mediated increased glycolysis

Project description:SARS-CoV-2 infection causes COVID-19, a severe acute respiratory disease associated with cardiovascular complications including long-term outcomes. The presence of virus in cardiac tissue of patients with COVID-19 suggests this is a direct, rather than secondary, effect of infection.Here, by expressing individual SARS-CoV-2 proteins in the Drosophila heart, we demonstrate interaction of virus Nsp6 with host proteins of the MGA/MAX complex (MGA, PCGF6 and TFDP1).

2022-10-04 | PXD036447 | Pride

NQO1 regulates inflammatory signaling

Project description:NQO1 silencing by a specific shRNA against NQO1 increased migration and hormone-independent survival in hormone-dependent human prostate cancer cells LNCaP. Genome wide array revealed that NQO1 blockade significantly upregulated pro-inflammatory mediators (e.g., IL-32, CCL2, IL-8, IL-17C, IL-10RA, CXCR2, CXCR7, NOS3) associated with prostate tumorigenesis. Two-condition experiment, control vs. NQO1 knockdown LNCaP cells. Biological replicates: 3 control replicates, 3 NQO1 knockdown replicates.

2014-08-26 | E-GEOD-58336 | biostudies-arrayexpress

Novel RNA-binding activity of NQO1 promotes SERPINA1 mRNA translation

Project description:NAD(P)H:quinone Oxidoreductase (NQO1) is essential for cell defense against reactive oxidative species, cancer, and metabolic stress. Recently, NQO1 was found in ribonucleoprotein (RNP) complexes, but NQO1-interacting mRNAs and the functional impact of such interactions are not known. Here, we used ribonucleoprotein immunoprecipitation (RIP) and microarray analysis to identify comprehensively the subset of NQO1 target mRNAs in human hepatoma HepG2 cells. One of its main targets, SERPINA1 mRNA, encodes the serine protease inhibitor α-1-antitrypsin, A1AT, which is associated with disorders including obesity-related metabolic inflammation, chronic obstructive pulmonary disease (COPD), liver cirrhosis and hepatocellular carcinoma. Biotin pulldown analysis indicated that NQO1 can bind the 3’ untranslated region (UTR) and the coding region (CR) of SERPINA1 mRNA. NQO1 did not affect SERPINA1 mRNA levels; instead, it enhanced the translation of SERPINA1 mRNA, as NQO1 silencing decreased the size of polysomes forming on SERPINA1 mRNA and lowered the abundance of A1AT. Luciferase reporter analysis further indicated that NQO1 regulates SERPINA1 mRNA translation through the SERPINA1 3’UTR. Accordingly, NQO1-KO mice had reduced hepatic and serum levels of A1AT and increased activity of neutrophil elastase, one of the main targets of A1AT. We propose that this novel mechanism of action of NQO1 as RNA-binding protein may help to explain its pleiotropic biological effects.

2017-05-22 | GSE81614 | GEO

NQO1 regulates inflammatory signaling

2014-08-26 | GSE58336 | GEO

Homo sapiens

Project description:NQO1 regulates inflammatory signaling

| PRJNA252018 | ENA

NQO1 regulates expression and alternative splicing of apoptotic genes associated with Alzheimer's disease in PC-12 cells

Project description:Quinone oxidoreductase I (NQO1), an important antioxidant enzyme which plays an important role in monitoring cellular redox state, was altered in the brain tissues of Alzheimer’s disease (AD) patients. In addition to its traditional antioxidant effect, NQO1 is also a multifunctional RNA-binding protein (RBP) in post-transcriptional regulation. However, NQO1 in AD pathology by acting as an RBP is not studied. In the present study, the RBP functions of NQO1 in rat PC12 cells, a cell line widely used in neurological disease studies, were investigated using siRNA knock-down (KD) and following whole transcriptome (RNA-seq) analysis. Reduced levels of NQO1 led to a significant increase in cellular apoptosis, compared with control cells. Notably, RNA-seq analysis of the transcriptome of PC12 cells by NQO1-KD revealed that genes in certain apoptosis pathways, were under global transcriptional and alternative splicing regulation. Quantitative RT-PCR confirmed the NQO1-regulated transcription of apoptotic genes Cryab, Lgmn , Ngf, Apoe, Brd7, Stat3, and alternative splicing of Bin1, Picalm, Fyn. These NQO1-regulated genes have been found to be closely related to AD pathogenesis. Our findings suggest that NQO1 acts as an RBP and participates in the pathology of AD by regulating expression and alternative splicing of genes involved in apoptosis. The results of present study extend our understanding of the cellular and molecular mechanisms in AD pathogenesis, which might contribute to the development of novel therapeutic targets.

2023-10-20 | GSE185633 | GEO

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