Inceptor binds to and directs insulin towards lysosomal degradation in β cells

verfasst von

Johanna Siehler, Sara Bilekova, Prisca Chapouton, Alessandro Dema, Pascal Albanese, Sem Tamara, Chirag Jain, Michael Sterr, Stephen J. Enos, Chunguang Chen, Chetna Malhotra, Adrian Villalba, Leopold Schomann, Sreya Bhattacharya, Jin Feng, Melis Akgün Canan, Federico Ribaudo, Ansarullah, Ingo Burtscher, Christin Ahlbrecht, Oliver Plettenburg, Thomas Kurth, Raphael Scharfmann, Stephan Speier, Richard A. Scheltema, Heiko Lickert

Abstract

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.

Organisationseinheit(en)

Institut für Organische Chemie
Zentrum für Biomolekulare Wirkstoffe (BMWZ)
Laboratorium für Nano- und Quantenengineering

Externe Organisation(en)

Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Deutsches Zentrum für Diabetesforschung e.V. (DZD)
Technische Universität München (TUM)
Utrecht University
Université Grenoble Alpes (UGA)
Proteomics Centre
Technische Universität Dresden
Universite Paris 5
Institute for Lung Health (ILH)
The University of Liverpool

Typ

Artikel

Journal

Nature Metabolism

Band

6

Seiten

2374-2390

Anzahl der Seiten

17

Publikationsdatum

25.11.2024

Publikationsstatus

Veröffentlicht

Peer-reviewed

Ja

ASJC Scopus Sachgebiete

Innere Medizin, Endokrinologie, Diabetes und Stoffwechsel, Physiologie (medizinische), Zellbiologie

Ziele für nachhaltige Entwicklung

SDG 3 – Gute Gesundheit und Wohlergehen

Elektronische Version(en)

https://doi.org/10.1038/s42255-024-01164-y (Zugang: Offen)