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 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.
Authors
- Luke E. Formosa (ORCID: https://orcid.org/0000-0002-7740-6151)
- Susanne S. Hille (ORCID: https://orcid.org/0000-0002-9809-4636)
- Maria Almira S. Cleofe
- Mathias Heikenwälder (ORCID: https://orcid.org/0000-0002-3135-2274)
- Yuqin Wu (ORCID: https://orcid.org/0000-0002-1762-1896)
- Terry C.C. Lim Kam Sian (ORCID: https://orcid.org/0000-0001-7038-1214)
- Adam J. Rose (ORCID: https://orcid.org/0000-0001-9132-8244)
- Cheng Huang (ORCID: https://orcid.org/0000-0002-4575-1233)
- Suchira Gallage (ORCID: https://orcid.org/0000-0002-1956-3597)
- Jared L. Johnson (ORCID: https://orcid.org/0000-0003-1802-6527)
- Lewis C. Cantley (ORCID: https://orcid.org/0000-0002-1298-7653)
- Tomer M. Yaron (ORCID: https://orcid.org/0000-0001-6574-7314)
- Oliver Josef Müller (ORCID: https://orcid.org/0000-0001-8223-2638)
- Andrea Y. Chan
- Matthew Challis (ORCID: https://orcid.org/0000-0002-9210-3095)
- Ralf B. Schittenhelm (ORCID: https://orcid.org/0000-0001-8738-1878)
- Patricia M. Rusu (ORCID: https://orcid.org/0000-0001-7210-1976)
- Mohammad Rahbari (ORCID: https://orcid.org/0000-0003-1133-2134)
- Ashish Foollee
- Greg C. Smith
- Victoria Mynard
- Jana Hauke
- Okka H Aung
- Jürgen G. Okun (ORCID: https://orcid.org/0000-0003-2975-1054)
Institutions
- Harvard University (US)
- German Cancer Research Center (DE)
- Cornell University (US)
- Heidelberg University (DE)
- Discovery Institute (US)
- University Hospital Heidelberg (DE)
- Lander Institute (IL)
- UNSW Sydney (AU)
- University Hospital Schleswig-Holstein (DE)
- Dana-Farber Cancer Institute (US)
- Monash Health (AU)
- German Centre for Cardiovascular Research (DE)
- University Medical Centre Mannheim (DE)
- Guided Therapeutics (United States) (US)
- Weill Cornell Medicine (US)
- Monash University (AU)
- Columbia University (US)
- University of Tübingen (DE)
- University of Lübeck (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-27
- DOI
- https://doi.org/10.1038/s41467-024-52703-w
- Citations
- 4
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 2.29
Funders
- University of Pennsylvania
- Wilhelm Sander-Stiftung
- Diabetes Australia Research Trust
- Diabetes Australia
- Endocrine Society of Australia
- Medical Research Council
- National Health and Medical Research Council