PXD040758 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Inceptor binds and directs insulin to lysosomal degradation in -cells |
Description | Blunted first-phase insulin secretion and insulin deficiency are early signs of -cell dysfunction and diabetes manifestation. Thus, insights into molecular mechanisms that regulate insulin homeostasis might provide entry sites to replenish insulin content and restore -cell function. Here, we identified the insulin inhibitory receptor (short: inceptor; encoded by the gene IIR) as an insulin-binding receptor that regulates insulin stores by lysosomal degradation. Using human induced pluripotent stem cell (iPSC)-derived islets, we show that IIR knockout (KO) results in enhanced stem cell (SC)--cell differentiation, maturation, and survival. Strikingly, extended in vitro culture of IIR KO SC--cells leads to greatly increased insulin content and glucose-stimulated insulin secretion (GSIS). We find inceptor localized to clathrin-coated vesicles close to the plasma membrane (PM) and in the trans-Golgi network (TGN), as well as in secretory granules (SGs), where it acts as a sorting receptor to direct proinsulin and insulin towards lysosomal degradation. Targeting inceptor using a monoclonal antibody increases insulin content and improves SC--cell function. Altogether, our findings revealed basic mechanisms of -cell insulin turnover and identified inceptor as a druggable insulin degradation receptor. |
HostingRepository | PRIDE |
AnnounceDate | 2024-09-09 |
AnnouncementXML | Submission_2024-09-09_07:03:15.925.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Richard Scheltema |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | No PTMs are included in the dataset |
Instrument | Q Exactive HF |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2023-03-10 00:52:35 | ID requested | |
⏵ 1 | 2024-09-09 07:03:16 | announced | |
2 | 2024-10-22 06:57:49 | announced | 2024-10-22: Updated project metadata. |
Publication List
Dataset with its publication pending |
Keyword List
submitter keyword: CDMS, Inceptor |
Contact List
Richard Scheltema |
contact affiliation | Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands; Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht |
contact email | r.a.scheltema@uu.nl |
lab head | |
Richard Scheltema |
contact affiliation | Utrecht University |
contact email | r.a.scheltema@uu.nl |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD040758
- Label: PRIDE project
- Name: Inceptor binds and directs insulin to lysosomal degradation in -cells