PXD040758-1

PXD040758 is an original dataset announced via ProteomeXchange.

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

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.

Dataset with its publication pending

submitter keyword: CDMS, Inceptor

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

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/09/PXD040758

PRIDE project URI

• PRIDE
  1. PXD040758
     1. Label: PRIDE project
     2. Name: Inceptor binds and directs insulin to lysosomal degradation in -cells