PuSH - Publication Server of Helmholtz Zentrum München

Siehler, J. ; Bilekova, S. ; Chapouton, P. ; Dema, A. ; Albanese, P.* ; Tamara, S.* ; Jain, C. ; Sterr, M. ; Enos, S.J. ; Chen, C. ; Malhotra, C. ; Villalba, A.* ; Schomann, L. ; Bhattacharya, S. ; Feng, J. ; Akgün, M. ; Ribaudo, F. ; Ansarullah ; Burtscher, I. ; Ahlbrecht, C. ; Plettenburg, O. ; Kurth, T.* ; Scharfmann, R.* ; Speier, S. ; Scheltema, R.A.* ; Lickert, H.

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

Nat. Metab., DOI: 10.1038/s42255-024-01164-y (2024)
Publ. Version/Full Text DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
Altmetric
Additional Metrics?
[➜Log in]
Edit extra informations Login
Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
ISSN (print) / ISBN 2522-5812
e-ISSN 2522-5812
Journal Nature metabolism
Publisher Springer
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Regeneration Research (IDR)
Institute for Pancreatic Beta Cell Research (IPI)
Institute of Medicinal Chemistry (IMC)