Phosphoproteomics-directed manipulation reveals SEC22B as a hepatocellular signaling node governing metabolic actions of glucagon.

Autor: Wu Y; Nutrient Metabolism & Signalling Laboratory, Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, Monash University, Victoria, Australia.; Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Faculty of Medicine, Nursing & Health Sciences, Monash University, Victoria, Australia., Foollee A; Nutrient Metabolism & Signalling Laboratory, Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, Monash University, Victoria, Australia.; Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Faculty of Medicine, Nursing & Health Sciences, Monash University, Victoria, Australia., Chan AY; Nutrient Metabolism & Signalling Laboratory, Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, Monash University, Victoria, Australia.; Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Faculty of Medicine, Nursing & Health Sciences, Monash University, Victoria, Australia., Hille S; Department of Internal Medicine V, University Hospital of Schleswig-Holstein, Campus Kiel, Germany.; German Center for Cardiovascular Research (DZHK), Partner site Hamburg/Kiel/Lübeck, Kiel, Germany., Hauke J; Division of Inherited Metabolic Diseases, University Children's Hospital, Heidelberg, Germany., Challis MP; Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Faculty of Medicine, Nursing & Health Sciences, Monash University, Victoria, Australia., Johnson JL; Meyer Cancer Center, Weill Cornell Medicine, New York, USA.; Department of Cell Biology, Harvard Medical School, Boston, USA.; Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA., Yaron TM; Meyer Cancer Center, Weill Cornell Medicine, New York, USA.; Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, USA.; Columbia University Vagelos College of Physicians and Surgeons, New York, USA., Mynard V; Nutrient Metabolism & Signalling Laboratory, Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, Monash University, Victoria, Australia.; Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Faculty of Medicine, Nursing & Health Sciences, Monash University, Victoria, Australia., Aung OH; Nutrient Metabolism & Signalling Laboratory, Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, Monash University, Victoria, Australia.; Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Faculty of Medicine, Nursing & Health Sciences, Monash University, Victoria, Australia., Cleofe MAS; Nutrient Metabolism & Signalling Laboratory, Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, Monash University, Victoria, Australia.; Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Faculty of Medicine, Nursing & Health Sciences, Monash University, Victoria, Australia., Huang C; Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Faculty of Medicine, Nursing & Health Sciences, Monash University, Victoria, Australia.; Monash Proteomics and Metabolomics Platform, Monash University, Victoria, Australia., Lim Kam Sian TCC; Monash Proteomics and Metabolomics Platform, Monash University, Victoria, Australia., Rahbari M; German Cancer Research Center (DKFZ), Division of Chronic Inflammation and Cancer, Im Neuenheimer Feld 280, Heidelberg, Germany.; University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Department of Surgery, Theodor-Kutzer-Ufer 1-3, Heidelberg, Germany.; University Tuebingen, Faculty of Medicine, Institute for Interdisciplinary Research on Cancer Metabolism and Chronic Inflammation, M3-Research Center for Malignome, Metabolome and Microbiome, Otfried-Müller-Straße 37, Tübingen, Germany., Gallage S; German Cancer Research Center (DKFZ), Division of Chronic Inflammation and Cancer, Im Neuenheimer Feld 280, Heidelberg, Germany.; University Tuebingen, Faculty of Medicine, Institute for Interdisciplinary Research on Cancer Metabolism and Chronic Inflammation, M3-Research Center for Malignome, Metabolome and Microbiome, Otfried-Müller-Straße 37, Tübingen, Germany., Heikenwalder M; German Cancer Research Center (DKFZ), Division of Chronic Inflammation and Cancer, Im Neuenheimer Feld 280, Heidelberg, Germany.; University Tuebingen, Faculty of Medicine, Institute for Interdisciplinary Research on Cancer Metabolism and Chronic Inflammation, M3-Research Center for Malignome, Metabolome and Microbiome, Otfried-Müller-Straße 37, Tübingen, Germany.; Cluster of Excellence iFIT (EXC 2180) 'Image-Guided and Functionally Instructed Tumor Therapies', Eberhard-Karls University, Tübingen, Germany., Cantley LC; Meyer Cancer Center, Weill Cornell Medicine, New York, USA.; Department of Cell Biology, Harvard Medical School, Boston, USA.; Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA., Schittenhelm RB; Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Faculty of Medicine, Nursing & Health Sciences, Monash University, Victoria, Australia.; Monash Proteomics and Metabolomics Platform, Monash University, Victoria, Australia., Formosa LE; Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Faculty of Medicine, Nursing & Health Sciences, Monash University, Victoria, Australia., Smith GC; School of Biomedical Sciences, University of New South Wales, Sydney, Australia., Okun JG; Division of Inherited Metabolic Diseases, University Children's Hospital, Heidelberg, Germany., Müller OJ; Department of Internal Medicine V, University Hospital of Schleswig-Holstein, Campus Kiel, Germany.; German Center for Cardiovascular Research (DZHK), Partner site Hamburg/Kiel/Lübeck, Kiel, Germany., Rusu PM; Nutrient Metabolism & Signalling Laboratory, Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, Monash University, Victoria, Australia.; Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Faculty of Medicine, Nursing & Health Sciences, Monash University, Victoria, Australia., Rose AJ; Nutrient Metabolism & Signalling Laboratory, Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, Monash University, Victoria, Australia. adam.rose@monash.edu.; Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Faculty of Medicine, Nursing & Health Sciences, Monash University, Victoria, Australia. adam.rose@monash.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Sep 27; Vol. 15 (1), pp. 8390. Date of Electronic Publication: 2024 Sep 27.
DOI: 10.1038/s41467-024-52703-w
Abstrakt: The peptide hormone glucagon is a fundamental metabolic regulator that is also being considered as a pharmacotherapeutic option for obesity and type 2 diabetes. Despite this, we know very little regarding how glucagon exerts its pleiotropic metabolic actions. Given that the liver is a chief site of action, we performed in situ time-resolved liver phosphoproteomics to reveal glucagon signaling nodes. Through pathway analysis of the thousands of phosphopeptides identified, we reveal "membrane trafficking" as a dominant signature with the vesicle trafficking protein SEC22 Homolog B (SEC22B) S137 phosphorylation being a top hit. Hepatocyte-specific loss- and gain-of-function experiments reveal that SEC22B was a key regulator of glycogen, lipid and amino acid metabolism, with SEC22B-S137 phosphorylation playing a major role in glucagon action. Mechanistically, we identify several protein binding partners of SEC22B affected by glucagon, some of which were differentially enriched with SEC22B-S137 phosphorylation. In summary, we demonstrate that phosphorylation of SEC22B is a hepatocellular signaling node mediating the metabolic actions of glucagon and provide a rich resource for future investigations on the biology of glucagon action.
(© 2024. The Author(s).)
Databáze: MEDLINE
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