Residues of the minimal sequence of G0S2 collectively contribute to ATGL inhibition while C-and N-terminal extensions promote binding to ATGL

Riegler-Berket, Lina; Wechselberger, Lisa; Cerk, Ines K.; Das, Krishna Mohan; Viertlmayr, Roland; Kulminskaya, Natalia; Gamez, C.F. Rodriguez; Schweiger, Martina; Zechner, Rudolf; Zimmermann, R.; Oberer, Monika

doi:10.1016/j.bbalip.2021.159105

Cited by 8 publications

(15 citation statements)

References 41 publications

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“…Regulation of ATGL activity on a protein level is very well studied with respect to the interaction of the proteins CGI-58, G0S2 and HILPDA [10][11][12][13][14][15][16]21,22]. Interestingly, the regulatory proteins are not conserved in all species [15,35]. Therefore, we performed an unbiased computational screen to identify amino acids within the sequence of ATGL that might affect its interaction with regulatory proteins.…”

Section: Results: Evolutionary Conservation Provides An Initial Ratio...mentioning

confidence: 99%

“…These residues are predominately surface-exposed and cluster on an almost continuous surface of the protein (Figure 1C). The amino acid exchanges were performed in a C-terminally truncated variant of mouse ATGL (mATGL288) [5,6,15,20,35]. We chose aromatic residues since these side-chains are frequently involved in biological interactions, whereas small alanine residues typically contribute very little to the protein-interactions.…”

Section: Results: Evolutionary Conservation Provides An Initial Ratio...mentioning

confidence: 99%

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Unmasking Crucial Residues in Adipose Triglyceride Lipase (ATGL) for Co-Activation with Comparative Gene Identification-58 (CGI-58)

Kulminskaya

Gamez

Hofer

et al. 2023

Preprint

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Lipolysis is an essential metabolic process that releases unesterified fatty acids from neutral lipid stores to maintain energy homeostasis in living organisms. Adipose triglyceride lipase (ATGL) plays a key role in intracellular lipolysis and can be co-activated upon interaction with the protein comparative gene identification-58 (CGI-58). The underlying molecular mechanism of ATGL/CGI-58 stimulation is incompletely understood. Based on analysis of evolutionary conservation we used site directed mutagenesis to study a C-terminally truncated variant and full-length mouse ATGL providing insights in the protein co-activation on a per-residue level. We identified the region from residues N209-N215 in mouse ATGL as essential for co-activation by mouse CGI-58. ATGL variants with amino-acids exchanges in this region were still able to hydrolyze triacylglycerol at the basal level and to interact with CGI-58, yet could not be co-activated by CGI-58. Our studies also demonstrate that full-length mouse ATGL showed higher tolerance to specific single amino acid exchanges in the N209-N215 region upon CGI-58 co-activation. The region is either directly involved in protein-protein interaction or essential for conformational changes required in the co-activation process. We generated three-dimensional models of the ATGL/CGI-58 complex with the artificial intelligence software AlphaFold demonstrating that a large surface area is involved in the protein-protein interaction. The model is in very good agreement with the herein presented data identifying important residues of ATGL and published data revealing essential residues of CGI-58 for co-activation.

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Section: Results: Evolutionary Conservation Provides An Initial Ratio...mentioning

confidence: 99%

Section: Results: Evolutionary Conservation Provides An Initial Ratio...mentioning

confidence: 99%

Unmasking Crucial Residues in Adipose Triglyceride Lipase (ATGL) for Co-Activation with Comparative Gene Identification-58 (CGI-58)

Kulminskaya

Gamez

Hofer

et al. 2023

Preprint

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“…103 In addition, G0/G1 switch 2 (G0S2) is a negative regulator of ATGL in adipocytes to reduce lipolysis. 104 Another neurotransmitter in the sympathetic nervous system, neuropeptide Y, also inhibits lipolysis through binding to inhibitory G protein-coupled receptors. 105 The acute or chronic peripheral administration of leptin stimulates TG hydrolysis in rat adipocytes by impairing insulin metabolism, which counteracts the antilipolytic effect of insulin.…”

Section: Tg Metabolism In Adipocytes Under Physiological Conditionsmentioning

confidence: 99%

“…Other hormones or cytokines, including glucocorticoids, thyroid hormones, growth hormones, ILs, TNFα, and leptin, can also affect lipase activity 103 . In addition, G0/G1 switch 2 (G0S2) is a negative regulator of ATGL in adipocytes to reduce lipolysis 104 . Another neurotransmitter in the sympathetic nervous system, neuropeptide Y, also inhibits lipolysis through binding to inhibitory G protein‐coupled receptors 105 .…”

Section: Lipid Metabolism In Adipocytes and Macrophages Under Physiol...mentioning

confidence: 99%

Inflammation‐mediated metabolic regulation in adipose tissue

Xu,

Lu,

Gao

et al. 2024

Obesity Reviews

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SummaryChronic inflammation of adipose tissue is a prominent characteristic of many metabolic diseases. Lipid metabolism in adipose tissue is consistently dysregulated during inflammation, which is characterized by substantial infiltration by proinflammatory cells and high cytokine concentrations. Adipose tissue inflammation is caused by a variety of endogenous factors, such as mitochondrial dysfunction, reactive oxygen species (ROS) production, endoplasmic reticulum (ER) stress, cellular senescence, ceramides biosynthesis and mediators of lipopolysaccharides (LPS) signaling. Additionally, the gut microbiota also plays a crucial role in regulating adipose tissue inflammation. Essentially, adipose tissue inflammation arises from an imbalance in adipocyte metabolism and the regulation of immune cells. Specific inflammatory signals, including nuclear factor‐κB (NF‐κB) signaling, inflammasome signaling and inflammation‐mediated autophagy, have been shown to be involved in the metabolic regulation. The pathogenesis of metabolic diseases characterized by chronic inflammation (obesity, insulin resistance, atherosclerosis and nonalcoholic fatty liver disease [NAFLD]) and recent research regarding potential therapeutic targets for these conditions are also discussed in this review.

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“…G0/G1 switch gene 2 (G0S2) is a multifunctional protein containing 103 amino acids, which is widely expressed and especially abundant in the heart, skeletal muscle, liver, kidney, brain, and adipose tissue (6). Previous studies have shown that G0S2 exists in the cytoplasm, endoplasmic reticulum, mitochondria, or lipid droplets at the subcellular levels, and plays different roles in different cellular contexts (7)(8)(9). G0S2 was first identified in activated lymphocytes and was related to the G0/G1 switch of cell cycle (10).…”

Section: Introductionmentioning

confidence: 99%

G0S2 ameliorates oxidized low-density lipoprotein-induced vascular endothelial cell injury by regulating mitochondrial apoptosis

Liang¹,

Diao²,

Jiang³

et al. 2022

Ann Transl Med

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Background: Oxidative low-density lipoprotein (ox-LDL)-induced endothelial cell damage is a major risk factor for atherosclerosis and its related cardiovascular diseases. The G0/G1 switch gene 2 (G0S2) is a multifunctional protein which has been poorly studied in atherosclerosis.Methods: In this study, ox-LDL was utilized to construct a human aortic endothelial cell (HAEC) injury model.Results: It was found that ox-LDL impaired cell viability, augmented lactate dehydrogenase (LDH) release, and reduced G0S2 levels in HAECs in a dose-dependent manner. Further, G0S2 overexpression improved the viability and restrained apoptosis of HAECs treated by ox-LDL. Conversely, G0S2 depletion decreased the viability and aggravated apoptosis of HAECs treated by ox-LDL. At the molecular level, G0S2 overexpression significantly increased the secretion of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPH-Px), promoted intracellular reactive oxygen species (ROS) production and malondialdehyde (MDA) content in HAECs under either normal or ox-LDL conditions. Meanwhile, the ox-LDL-induced mitochondrial dysfunction, as demonstrated by decreased mitochondrial membrane potential, translocation of mitochondrial cytochrome c (Cyt-c) to the cytoplasm, and activation of caspase-3 and caspase-9, was significantly reversed by G0S2 overexpression. In addition, G0S2 overexpression promoted the activation of AMP-activated protein kinase (AMPK) and increased the expression of nuclear factor erythroid-2-related factor-2 (Nrf2), sirtuin 1 (SIRT1) and heme oxygenase 1 (HO-1) under normal and ox-LDL conditions.Conclusions: This study demonstrated that G0S2 protects against ox-LDL-induced vascular endothelial cell injury by regulating oxidative damage and mitochondrial homeostasis and may be a promising target for the treatment of atherosclerosis.

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Residues of the minimal sequence of G0S2 collectively contribute to ATGL inhibition while C-and N-terminal extensions promote binding to ATGL

Cited by 8 publications

References 41 publications

Unmasking Crucial Residues in Adipose Triglyceride Lipase (ATGL) for Co-Activation with Comparative Gene Identification-58 (CGI-58)

Unmasking Crucial Residues in Adipose Triglyceride Lipase (ATGL) for Co-Activation with Comparative Gene Identification-58 (CGI-58)

Inflammation‐mediated metabolic regulation in adipose tissue

G0S2 ameliorates oxidized low-density lipoprotein-induced vascular endothelial cell injury by regulating mitochondrial apoptosis

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