PXD056782-1

PXD056782 is an original dataset announced via ProteomeXchange.

Title	GLP-1R associates with VAPB and SPHKAP at ERMCSs to regulate β-cell mitochondrial remodelling and function
Description	Glucagon-like peptide-1 receptor (GLP-1R) agonists (GLP-1RAs) ameliorate mitochondrial health by increasing mitochondrial turnover in metabolically relevant tissues. Mitochondrial adaptation to metabolic stress is crucial to maintain pancreatic -cell function and prevent type 2 diabetes (T2D) progression. While the GLP-1R is well-known to stimulate cAMP production leading to Protein Kinase A (PKA) and Exchange Protein Activated by cyclic AMP 2 (Epac2) activation, there is a lack of understanding of the molecular mechanisms linking GLP-1R signalling with mitochondrial and -cell functional adaptation. Here, we present a comprehensive study in -cell lines and primary islets that demonstrates that, following GLP-1RA stimulation, GLP-1R-positive endosomes associate with the endoplasmic reticulum (ER) membrane contact site (MCS) tether VAPB at ER-mitochondria MCSs (ERMCSs), where active GLP-1R engages with SPHKAP, an A-kinase anchoring protein (AKAP) previously linked to T2D and adiposity risk in genome-wide association studies (GWAS). The inter-organelle complex formed by endosomal GLP-1R, ER VAPB and SPHKAP triggers a pool of ERMCS-localised cAMP/PKA signalling via the formation of a PKA-RIα biomolecular condensate which leads to changes in mitochondrial contact site and cristae organising system (MICOS) complex phosphorylation, mitochondrial remodelling, and -cell functional adaptation, with important consequences for the regulation of -cell insulin secretion and survival to stress.
HostingRepository	PRIDE
AnnounceDate	2025-09-30
AnnouncementXML	Submission_2025-09-30_03:32:51.074.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Alex Montoya
SpeciesList	scientific name: Rattus norvegicus (Rat); NCBI TaxID: 10116;
ModificationList	2-pyrrolidone-5-carboxylic acid (Gln); acetylated residue; monohydroxylated residue; deamidated residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2024-10-14 06:44:03	ID requested
⏵ 1	2025-09-30 03:32:51	announced

Dataset with its publication pending

submitter keyword: membrane contact sites, pancreatic beta cells, mitochondrial remodelling, AKAPs, ER-mitochondrial contacts, incretins, SPHKAP, compartmentalised PKA signalling,GLP-1R, VAP-B

Alex Montoya
contact affiliation	MRC-Laboratory of Medical Sciences
contact email	alex.montoya@lms.mrc.ac.uk
lab head
Alex Montoya
contact affiliation	Medical Research Council - London Institute of Medical Sciences
contact email	alex.montoya@lms.mrc.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD056782
     1. Label: PRIDE project
     2. Name: GLP-1R associates with VAPB and SPHKAP at ERMCSs to regulate β-cell mitochondrial remodelling and function