Nature Communications (Sep 2024)

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

  • 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,
  • Terry C. C. Lim Kam Sian,
  • Mohammad Rahbari,
  • Suchira Gallage,
  • Mathias Heikenwalder,
  • Lewis C. Cantley,
  • Ralf B. Schittenhelm,
  • Luke E. Formosa,
  • Greg C. Smith,
  • Jürgen G. Okun,
  • Oliver J. Müller,
  • Patricia M. Rusu,
  • Adam J. Rose

DOI
https://doi.org/10.1038/s41467-024-52703-w
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 17

Abstract

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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.