Proteogenomic Discovery of Novel Open Reading Frames With HLA Immune Presentation on Human β-Cells
We developed a cell type-specific proteogenomic approach to reveal novel or unannotated open reading frames (nuORFs) using transcriptomics, ribosomal profiling, and proteomic analysis of human pancreatic β-cells using stem cell-derived β-cells and/or cadaveric islets. Our analysis revealed translational regulation of β-cell-specific pathways during differentiation and identified 965 nuORFs, with a majority exhibiting protein support and substantial β-cell specificity. A primate-specific ORF located in the 5' untranslated region of the type 1 diabetes risk gene TYK2 may act as a translational activator. We provide HLA class I immunopeptidomic data from cytokine-stimulated human β-cells and demonstrate their utility in coculture assays with autoreactive T-cell transductants. Taken together, our results define the human β-cell translatome, an important resource to the research field.
Authors
- Amber Baldwin (ORCID: https://orcid.org/0000-0002-7346-3052)
- Ann Sullivan Baker
- Holger A. Russ (ORCID: https://orcid.org/0000-0001-5117-2927)
- Maki Nakayama (ORCID: https://orcid.org/0000-0002-0009-3687)
- Soumyadeep Sarkar (ORCID: https://orcid.org/0000-0002-1928-1848)
- Roberto Castro-Gutiérrez (ORCID: https://orcid.org/0000-0001-5873-6473)
- Ernesto Satoshi Nakayasu (ORCID: https://orcid.org/0000-0002-4056-2695)
- Ali H. Shilleh (ORCID: https://orcid.org/0000-0002-5092-5744)
- A. Anderson (ORCID: https://orcid.org/0000-0001-9746-1257)
- Kathryn Walters (ORCID: https://orcid.org/0000-0001-6562-6889)
- Neelanjan Mukherjee (ORCID: https://orcid.org/0000-0003-0017-1400)
- Tim Fugman
Institutions
- Pacific Northwest National Laboratory (US)
- University of Freiburg (DE)
- Justus-Liebig-Universität Gießen (DE)
- University of Florida (US)
- Reaction Biology (Germany) (DE)
- Oxford Centre for Diabetes, Endocrinology and Metabolism (GB)
- University of Colorado Anschutz Medical Campus (US)
- Florida College (US)
Publication Details
- Journal
- Diabetes
- Published
- 2025-09-02
- DOI
- https://doi.org/10.2337/db24-0527
- Citations
- 1
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 2.01
Funders
- U.S. Department of Energy
- Boettcher Foundation
- Endocrine Society
- Environmental Molecular Sciences Laboratory
- National Institutes of Health
- Anschutz Medical Campus, University of Colorado
- National Institute of Diabetes and Digestive and Kidney Diseases