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

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...

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Main Authors: Wu, Yuqin (Author) , Foollee, Ashish (Author) , Chan, Andrea Y. (Author) , Hille, Susanne (Author) , Hauke, Jana (Author) , Challis, Matthew P. (Author) , Johnson, Jared L. (Author) , Yaron, Tomer M. (Author) , Mynard, Victoria (Author) , Aung, Okka H. (Author) , Cleofe, Maria Almira S. (Author) , Huang, Cheng (Author) , Lim Kam Sian, Terry C. C. (Author) , Rahbari, Mohammad (Author) , Gallage, Suchira (Author) , Heikenwälder, Mathias (Author) , Cantley, Lewis C. (Author) , Schittenhelm, Ralf B. (Author) , Formosa, Luke E. (Author) , Smith, Greg C. (Author) , Okun, Jürgen G. (Author) , Müller, Oliver J. (Author) , Rusu, Patricia M. (Author) , Rose, Adam J. (Author)
Format: Article (Journal)
Language:English
Published: 27 September 2024
In: Nature Communications
Year: 2024, Volume: 15, Pages: 1-17
ISSN:2041-1723
DOI:10.1038/s41467-024-52703-w
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-024-52703-w
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-024-52703-w
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Author Notes: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

MARC

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520 |a 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. 
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