PXD052042-1

PXD052042 is an original dataset announced via ProteomeXchange.

Title	Cab45-dependent facilitation of insulin secretory granule biogenesis and its dysregulation in type 2 diabetes
Description	Germanos M1*. Yau B1*. Taper M1. An Y1. Yeoman C1. Wilson A1. Cattin-Ortolá J2. Maslar D3. Tong J1. Naghiloo S1. Needham E4. Diaz-Vegas A4. Larance M1. Thomas H5. Seidah NG6. von Blume J7. James DE4. Thorn P1. Ailion M2. Asensio C3. Kebede MA1. 1 School of Medical Sciences, Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia. 2 Department of Biochemistry, University of Washington, Seattle, WA USA. 3 Department of Biological Sciences, University of Denver, Denver, Colorado 80210, United States. 4 Discipline of Biochemistry and Molecular Biology, School of Life and Environmental Sciences, Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia. 5 Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, Melbourne, Victoria, Australia. 6 Laboratory of Biochemical Neuroendocrinology, Institut de Recherches Cliniques de Montréal, Montreal, QC, Canada. 7 Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06510.. *These authors contributed equally. Abstract Here we investigate the role of Cab45 in β-cell function and insulin secretory granule (ISG) biogenesis. Cab45 has been known as a ubiquitously expressed, soluble, trans-Golgi network (TGN) resident protein. We demonstrate its expression in pancreatic islets but not exocrine tissue, and localization in both Golgi and granular/vesicular compartments of primary β-cells. In INS1 cells, Cab45 is held in the cis-Golgi by a calcium-dependent mechanism but is capable of anterograde trafficking beyond the TGN. ISG biogenesis is maintained in Cab45 knockout INS1 cells which exhibit insulin hypersecretion due to dysregulated calcium homeostasis, leading to ISG depletion that is reinstated by rest at low glucose or Cab45 overexpression. Overexpressed Cab45 traffics directly into ISGs and increases biogenesis. Expression of a Cab45 variant that cannot bind calcium drives superior ISG rescue and has reduced ISG residency. In humans, anterograde Cab45 trafficking increases with worsening obesity, suggesting recruitment to drive cargo transit and support secretory output. Humans with type 2 diabetes, however, contain a greater proportion of Cab45-occupied ISGs and a loss of Golgi-localized Cab45 compared to non-diabetics. These insights position Cab45 as an exciting candidate for further investigation into mechanisms associated with β-cell compensation and failure.
HostingRepository	PRIDE
AnnounceDate	2024-12-02
AnnouncementXML	Submission_2024-12-01_20:25:02.854.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mark Larance
SpeciesList	scientific name: Rattus rattus (Black rat); NCBI TaxID: 10117;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF; Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2024-05-06 22:17:12	ID requested
⏵ 1	2024-12-01 20:25:03	announced

Dataset with its publication pending

submitter keyword: islet,CAB45, insulin

Mark Larance
contact affiliation	Charles Perkins Centre, School of Medical Sciences, University of Sydney, Sydney, Australia.
contact email	mark.larance@sydney.edu.au
lab head
Mark Larance
contact affiliation	The University of Sydney
contact email	mark.larance@sydney.edu.au
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD052042
     1. Label: PRIDE project
     2. Name: Cab45-dependent facilitation of insulin secretory granule biogenesis and its dysregulation in type 2 diabetes