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- Title
Cathepsin D Drives the Formation of Hybrid Insulin Peptides Relevant to the Pathogenesis of Type 1 Diabetes.
- Authors
Crawford, Samantha A.; Wiles, Timothy A.; Wenzlau, Janet M.; Powell, Roger L.; Barbour, Gene; Dang, Mylinh; Groegler, Jason; Barra, Jessie M.; Burnette, KaLia S.; Hohenstein, Anita C.; Baker, Rocky L.; Tse, Hubert M.; Haskins, Kathryn; Delong, Thomas
- Abstract
Hybrid insulin peptides (HIPs) form in pancreatic β-cells through the formation of peptide bonds between proinsulin fragments and other peptides. HIPs have been identified in pancreatic islets by mass spectrometry and are targeted by CD4 T cells in patients with type 1 diabetes (T1D) as well as by pathogenic CD4 T-cell clones in nonobese diabetic (NOD) mice. The mechanism of HIP formation is currently poorly understood; however, it is well established that proteases can drive the formation of new peptide bonds in a side reaction during peptide bond hydrolysis. Here, we used a proteomic strategy on enriched insulin granules and identified cathepsin D (CatD) as the primary protease driving the specific formation of HIPs targeted by disease-relevant CD4 T cells in T1D. We also established that NOD islets deficient in cathepsin L (CatL), another protease implicated in the formation of disease-relevant HIPs, contain elevated levels of HIPs, indicating a role for CatL in the proteolytic degradation of HIPs. In summary, our data suggest that CatD may be a therapeutic target in efforts to prevent or slow the autoimmune destruction of β-cells mediated by HIP-reactive CD4 T cells in T1D.
- Subjects
TYPE 1 diabetes; PROTEOLYTIC enzymes; INSULIN; PROTEOMICS; T cells; MICE; ANIMALS; PEPTIDES
- Publication
Diabetes, 2022, Vol 71, Issue 12, p2793
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db22-0303