Deep mutational interaction perturbation reveals ATGL contact sites with key regulatory proteins in lipolysis
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ABSTRACT:
PROVIDER: PRJEB60025 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR11532719_1.fastq.gz | Fastqsanger.gz | |||
| ERR11532719_2.fastq.gz | Fastqsanger.gz | |||
| ERR11532720_1.fastq.gz | Fastqsanger.gz | |||
| ERR11532720_2.fastq.gz | Fastqsanger.gz | |||
| ERR11532721_1.fastq.gz | Fastqsanger.gz |
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Project description:ATGL is the key enzyme in intracellular lipolysis playing a critical role in metabolic and cardiovascular diseases. ATGL is tightly regulated through a known set of protein-protein interaction partners with activating or inhibiting functions in control of lipolysis. However, the binding mode and protein interaction sites of ATGL and its partners are unknown. Using deep mutational protein interaction perturbation scanning we generated comprehensive profiles of single amino acid variants effecting the interactions of ATGL with its regulatory partners: CGI-58, G0S2, PLIN1, PLIN5 and CIDEC. Twenty-three ATGL variants gave a specific interaction perturbation pattern when validated in co-immunoprecipitation experiments in mammalian cells. We identified and characterized eleven, highly selective ATGL “switch” mutations which affect the interaction of one of the five partners without affecting the others. Switch mutations thus provided distinct interaction determinants for ATGL’s key regulatory proteins at an amino acid resolution. When tested for triglyceride hydrolase activity in vitro and lipolysis in cells, the activity patterns of the ATGL switch variants traced to their protein interaction profile. In the context of structural data, the integration of variant binding and activity profiles provided important insights into lipolysis regulation and the impact of mutations in human disease.
2024-03-14 | PXD049436 | Pride
Project description:ATGL is a key enzyme in intracellular lipolysis and plays an important role in metabolic and cardiovascular diseases. ATGL is tightly regulated by a known set of protein-protein interaction partners with activating or inhibiting functions in the control of lipolysis. Here, we use deep mutational protein interaction perturbation scanning and generate comprehensive profiles of single amino acid variants that affect the interactions of ATGL with its regulatory partners: CGI-58, G0S2, PLIN1, PLIN5 and CIDEC. Twenty-three ATGL amino acid variants yield a specific interaction perturbation pattern when validated in co-immunoprecipitation experiments in mammalian cells. We identify and characterize eleven highly selective ATGL switch mutations which affect the interaction of one of the five partners without affecting the others. Switch mutations thus provide distinct interaction determinants for ATGL's key regulatory proteins at an amino acid resolution. When we test triglyceride hydrolase activity in vitro and lipolysis in cells, the activity patterns of the ATGL switch variants trace to their protein interaction profile. In the context of structural data, the integration of variant binding and activity profiles provides insights into the regulation of lipolysis and the impact of mutations in human disease.
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Project description:ATGL= the rate-limiting enzyme for intracellular lipolysis. Atgl KO/cTg = Mice lacking Atgl except for cardiac transgenic overexpression of Atgl (Atgl -/- ,Myh6Atgl+/+) to rescue early age death deu to cardiomyopathy. wt/cTg = respective control. The airways of the lung are constantly exposed to inhaled toxic substances, resulting in cellular damage. Within bronchii, club cells make up majority of the cell population in the terminal bronchiolar epithelia. Club cells are known for their ability to metabolize environmental toxins and constantly repairing small impacts in the epithelial layer. Considering the importance of club cells in maintaining bronchiolar epithelial integrity, we porformed gene expression data analysis to decipher the possible dysregulated gene expression thereby corresponding molecular pathways in our mice lacking ATGL.
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Project description:Lipid metabolism plays a central role in prostate cancer. To date, the major focus on prostate cancer lipid metabolism has centered on the roles of de novo lipogenesis and lipid uptake with little consideration for how cancer cells access these lipids once they are created or taken up and stored. Analysis of patient-derived phosphoproteomics data identified adipose triglyceride lipase (ATGL), a rate-limiting enzyme in the breakdown of triglycerides and previously suspected tumor suppressor, as a target of calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2)-AMP-dependent protein kinase (AMPK) signaling that, conversely, promotes castration-resistant prostate cancer (CRPC) progression. Phosphorylation of ATGL by CAMKK2-AMPK signaling increased ATGL’s lipase activity, cancer cell proliferation, migration, and invasion. Shotgun lipidomics and imaging mass spectrometry demonstrated ATGL’s profound regulation of prostate cancer lipid metabolism in vitro and in vivo, remodeling membrane composition. Targeting ATGL using molecular, genetic, and/or pharmacological approaches impaired the growth of human and murine prostate cancer cells in culture and xenograft mouse models of CRPC as well as organoid models. The efficacy of ATGL inhibition occurs in a glucose concentration-dependent manner. Accordingly, pharmacological inhibition or depletion of ATGL induced metabolic plasticity with a shift towards glycolysis, which could be exploited therapeutically by co-targeting both metabolic pathways. Together, these data nominate ATGL and intracellular lipolysis as a potential therapeutic target for the treatment of CRPC and provide insights for future combination therapies.
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Project description:Obesity is a worldwide epidemic associated with increased risk and progression of colon cancer. Here, we aimed to determine the role of adipose triglyceride lipase (ATGL), responsible for intracellular lipid droplet (LDs) utilization, in obesity driven colonic tumorigenesis. In local colon cancer patients, significantly increased ATGL levels in tumor tissue, compared to controls, were augmented in obese individuals. Elevated ATGL levels in human colon cancer cells (CCC) relative to non-transformed were augmented by an obesity mediator, oleic acid (OA). In CCC and colonospheres, enriched in colon cancer stem cells (CCSC), inhibition of ATGL prevented LDs utilization and inhibited OA-stimulated growth through retinoblastoma-mediated cell-cycle arrest. Further, transcriptomic analysis of CCC, with inhibited ATGL, revealed targeted pathways driving tumorigenesis and high-fat-diet obesity facilitated tumorigenic pathways. Inhibition of ATGL in colonospheres revealed targeted pathways in human colonic tumor crypt base cells (enriched in CCSC) derived from colon cancer patients. In CCC and colonospheres, we validated selected transcripts targeted by ATGL inhibition, some with emerging roles in colonic tumorigeneses (ATG2B, PCK2, PGAM1, SPTLC2, IGFBP1, ABCC3) and others with established roles (MYC, MUC2). These findings demonstrate obesity-promoted, ATGL-mediated colonic tumorigenesis and establishes therapeutic significance of ATGL in obesity reinforced colon cancer progression.
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