Inceptor binds to and directs insulin towards lysosomal degradation in β cells
Blunted first-phase insulin secretion and insulin deficiency are indicators of β cell dysfunction and diabetes manifestation. Therefore, insights into molecular mechanisms that regulate insulin homeostasis might provide entry sites to replenish insulin content and restore β cell function. Here, we identify the insulin inhibitory receptor (inceptor; encoded by the gene IIR/ELAPOR1) as an insulin-binding receptor that regulates insulin stores by lysosomal degradation. Using human induced pluripotent stem cell (SC)-derived islets, we show that IIR knockout (KO) results in enhanced SC β cell differentiation and survival. Strikingly, extended in vitro culture of IIR KO SC β cells leads to greatly increased insulin content and glucose-stimulated insulin secretion (GSIS). We find that inceptor localizes to clathrin-coated vesicles close to the plasma membrane and in the trans-Golgi network as well as in secretory granules, where it acts as a sorting receptor to direct proinsulin and insulin towards lysosomal degradation. Targeting inceptor using a monoclonal antibody increases proinsulin and insulin content and improves SC β cell GSIS. Altogether, our findings reveal the basic mechanisms of β cell insulin turnover and identify inceptor as an insulin degradation receptor.
Authors
- Johanna Siehler
- Jin Feng (ORCID: https://orcid.org/0000-0001-7265-0051)
- Raphaël Scharfmann (ORCID: https://orcid.org/0000-0001-7619-337X)
- Pascal Albanese (ORCID: https://orcid.org/0000-0002-0940-8534)
- Sem Tamara (ORCID: https://orcid.org/0000-0002-6062-9404)
- Michael Sterr
- Chirag Jain (ORCID: https://orcid.org/0000-0002-9205-3737)
- Oliver Plettenburg (ORCID: https://orcid.org/0000-0001-9671-278X)
- Christin Ahlbrecht
- Stephan Speier (ORCID: https://orcid.org/0000-0002-4561-7085)
- Chunguang Chen
- Sreya Bhattacharya
- Federico Ribaudo
- Sara Bilekova (ORCID: https://orcid.org/0000-0001-6699-1386)
- Alessandro Dema (ORCID: https://orcid.org/0000-0003-0976-9396)
- Thomas Kurth (ORCID: https://orcid.org/0000-0001-5624-1717)
- Heiko Lickert (ORCID: https://orcid.org/0000-0002-4597-8825)
- Adrian Villalba (ORCID: https://orcid.org/0000-0003-3148-5453)
- Chetna Malhotra (ORCID: https://orcid.org/0000-0002-5380-0525)
- Richard A. Scheltema (ORCID: https://orcid.org/0000-0002-1668-0253)
- Stephen J. Enos (ORCID: https://orcid.org/0000-0003-1026-1418)
- Ingo Burtscher
- Prisca Chapouton (ORCID: https://orcid.org/0000-0002-5281-153X)
- Leopold Schomann (ORCID: https://orcid.org/0009-0008-6716-1753)
- Melis Akgün Canan
- Md Ansarullah
Institutions
- Leibniz University Hannover (DE)
- Centre National de la Recherche Scientifique (FR)
- University of Liverpool (GB)
- Inserm (FR)
- Utrecht University (NL)
- Université Paris Cité (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Helmholtz Zentrum München (DE)
- CEA Grenoble (FR)
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR)
- Institut Cochin (FR)
- Center for Systems Biology Dresden (DE)
- Target (Germany) (DE)
- Deutsches Diabetes-Zentrum e.V. (DE)
- German Center for Diabetes Research (DE)
- University Hospital Carl Gustav Carus (DE)
- Paul Langerhans Institute Dresden (DE)
- Heinrich Heine University Düsseldorf (DE)
- Technical University of Munich (DE)
- Université Grenoble Alpes (FR)
Publication Details
- Journal
- Nature Metabolism
- Published
- 2024-11-25
- DOI
- https://doi.org/10.1038/s42255-024-01164-y
- Citations
- 9
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 5.15