ArticleThe Journal of experimental medicine2021
Lysosomal cathepsin creates chimeric epitopes for diabetogenic CD4 T cells via transpeptidation.
Article in The Journal of experimental medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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45 citing papers in PubMed, 56 citations in OpenAlex.
- Integrative transcriptomic and machine learning analysis identifies PYCARD and IFI30 as immune-lysosomal biomarkers of ANCA-associated glomerulonephritis.Renal failure · 2026Article
- Discovery of Post-Translationally Modified Epitopes in Autoimmunity: Someone Has to Fish so Everyone Can Eat.Immunological reviews · 2026Review
- Beyond Sequence: Posttranslational Remodeling of Antigens in Autoimmunity.Immunological reviews · 2026Review
- Crinophagy in Pancreatic Beta Cells: From Insulin Granule Turnover to Diabetes Pathogenesis.Pathophysiology : the official journal of the International Society for Pathophysiology · 2026Review
- Ubiquitination of secretory granules promotes their crinophagic degradation in Drosophila.FEBS letters · 2026Article
- A multi-level machine learning pipeline for prediction and prioritization of hybrid insulin peptides in type 1 diabetes.Frontiers in immunology · 2026Article
- The role of chromogranin A cleavage products in onset of type 1 and 2 diabetes.Frontiers in clinical diabetes and healthcare · 2026Review
- Proteasome-derived peptides: separating the trash from the recycling.Trends in biochemical sciences · 2025Review
- Type 1 Diabetes: A Guide to Autoimmune Mechanisms for Clinicians.Diabetes, obesity & metabolism · 2025Review
- Disease-modifying pharmacological treatments of type 1 diabetes: Molecular mechanisms, target checkpoints, and possible combinatorial treatments.Pharmacological reviews · 2025Review
- Nanoparticle platform preferentially targeting liver sinusoidal endothelial cells induces tolerance in CD4+ T cell-mediated disease models.Frontiers in immunology · 2025Article
- Proinsulin C-peptide is a major source of HLA-DQ8 restricted hybrid insulin peptides recognized by human islet-infiltrating CD4PNAS nexus · 2024Article
- CD4Immunity · 2024Article
- Lysosomal physiology and pancreatic lysosomal stress in diabetes mellitus.eGastroenterology · 2024Article
- Crinophagic granules in pancreatic β cells contribute to mouse autoimmune diabetes by diversifying pathogenic epitope repertoire.Nature communications · 2024Article
- Protein degradation by human 20S proteasomes elucidates the interplay between peptide hydrolysis and splicing.Nature communications · 2024Article
- Mapping of a hybrid insulin peptide in the inflamed islet β-cells from NOD mice.Frontiers in immunology · 2024Article
- Antigen-specific T cell responses in autoimmune diabetes.Frontiers in immunology · 2024Review
- β Cell Stress and Endocrine Function During T1D: What Is Next to Discover?Endocrinology · 2023Article
- Identification of Autoantibodies to a Hybrid Insulin Peptide in Type 1 Diabetes.Diagnostics (Basel, Switzerland) · 2023Article
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Authors and funding
9 authors at 2 institutions in 1 country.
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Abstract
The identification of the peptide epitopes presented by major histocompatibility complex class II (MHCII) molecules that drive the CD4 T cell component of autoimmune diseases has presented a formidable challenge over several decades. In type 1 diabetes (T1D), recent insight into this problem has come from the realization that several of the important epitopes are not directly processed from a protein source, but rather pieced together by fusion of different peptide fragments of secretory granule proteins to create new chimeric epitopes. We have proposed that this fusion is performed by a reverse proteolysis reaction called transpeptidation, occurring during the catabolic turnover of pancreatic proteins when secretory granules fuse with lysosomes (crinophagy). Here, we demonstrate several highly antigenic chimeric epitopes for diabetogenic CD4 T cells that are produced by digestion of the appropriate inactive fragments of the granule proteins with the lysosomal protease cathepsin L (Cat-L). This pathway has implications for how self-tolerance can be broken peripherally in T1D and other autoimmune diseases.
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