American Diabetes Association
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Cathepsin D drives the formation of hybrid insulin peptides relevant to the pathogenesis of type 1 diabetes

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posted on 2022-08-30, 20:27 authored by Samantha A. Crawford, Timothy A. Wiles, Janet M. Wenzlau, Roger L. Powell, Gene Barbour, Mylinh Dang, Jason Groegler, Jessie M. Barra, KaLia S. Burnette, Anita C. Hohenstein, Rocky L. Baker, Hubert M. Tse, Kathryn Haskins, Thomas Delong

Hybrid insulin peptides (HIPs) form in pancreatic beta-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 non-obese 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 down the autoimmune destruction of beta-cells mediated by HIP-reactive CD4 T cells in T1D. 


This work was supported by NIH R01 grants DK119529 (T.D.), DK081166 (K.H.), DK126456 (H.M.T.), and DK127497 (H.M.T.).