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

Author

Listed:
  • Yuqin Wu

    (Monash University
    Monash University)

  • Ashish Foollee

    (Monash University
    Monash University)

  • Andrea Y. Chan

    (Monash University
    Monash University)

  • Susanne Hille

    (University Hospital of Schleswig-Holstein
    Partner site Hamburg/Kiel/Lübeck)

  • Jana Hauke

    (University Children’s Hospital)

  • Matthew P. Challis

    (Monash University)

  • Jared L. Johnson

    (Weill Cornell Medicine
    Harvard Medical School
    Harvard Medical School)

  • Tomer M. Yaron

    (Weill Cornell Medicine
    Weill Cornell Medicine
    Columbia University Vagelos College of Physicians and Surgeons)

  • Victoria Mynard

    (Monash University
    Monash University)

  • Okka H. Aung

    (Monash University
    Monash University)

  • Maria Almira S. Cleofe

    (Monash University
    Monash University)

  • Cheng Huang

    (Monash University
    Monash University)

  • Terry C. C. Lim Kam Sian

    (Monash University)

  • Mohammad Rahbari

    (Im Neuenheimer Feld 280
    Theodor-Kutzer-Ufer 1-3
    Otfried-Müller-Straße 37)

  • Suchira Gallage

    (Im Neuenheimer Feld 280
    Otfried-Müller-Straße 37)

  • Mathias Heikenwalder

    (Im Neuenheimer Feld 280
    Otfried-Müller-Straße 37
    Eberhard-Karls University)

  • Lewis C. Cantley

    (Weill Cornell Medicine
    Harvard Medical School
    Harvard Medical School)

  • Ralf B. Schittenhelm

    (Monash University
    Monash University)

  • Luke E. Formosa

    (Monash University)

  • Greg C. Smith

    (University of New South Wales)

  • Jürgen G. Okun

    (University Children’s Hospital)

  • Oliver J. Müller

    (University Hospital of Schleswig-Holstein
    Partner site Hamburg/Kiel/Lübeck)

  • Patricia M. Rusu

    (Monash University
    Monash University)

  • Adam J. Rose

    (Monash University
    Monash University)

Abstract

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.

Suggested Citation

  • Yuqin Wu & Ashish Foollee & Andrea Y. Chan & Susanne Hille & Jana Hauke & Matthew P. Challis & Jared L. Johnson & Tomer M. Yaron & Victoria Mynard & Okka H. Aung & Maria Almira S. Cleofe & Cheng Huang, 2024. "Phosphoproteomics-directed manipulation reveals SEC22B as a hepatocellular signaling node governing metabolic actions of glucagon," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52703-w
    DOI: 10.1038/s41467-024-52703-w
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    References listed on IDEAS

    as
    1. Yann W. Yap & Patricia M. Rusu & Andrea Y. Chan & Barbara C. Fam & Andreas Jungmann & Samantha M. Solon-Biet & Christopher K. Barlow & Darren J. Creek & Cheng Huang & Ralf B. Schittenhelm & Bruce Morg, 2020. "Restriction of essential amino acids dictates the systemic metabolic response to dietary protein dilution," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    2. Rachel J. Perry & Dongyan Zhang & Mateus T. Guerra & Allison L. Brill & Leigh Goedeke & Ali R. Nasiri & Aviva Rabin-Court & Yongliang Wang & Liang Peng & Sylvie Dufour & Ye Zhang & Xian-Man Zhang & Gi, 2020. "Glucagon stimulates gluconeogenesis by INSP3R1-mediated hepatic lipolysis," Nature, Nature, vol. 579(7798), pages 279-283, March.
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