Nardilysin-dependent proteolysis of cell-associated VTCN1 (B7-H4) marks type 1 diabetes development.

T-cell responses directed against insulin-secreting pancreatic β-cells are the key events highlighting type 1 diabetes (T1D). Therefore, a defective control of T-cell activation is thought to underlie T1D development. Recent studies implicated a B7-like negative costimulatory protein, V-set domain-containing T-cell activation inhibitor-1 (VTCN1), as a molecule capable of inhibiting T-cell activation and, potentially, an important constituent in experimental models of T1D. Here, we unravel a general deficiency within the VTCN1 pathway that is shared between diabetes-prone mice and a subset of T1D patients. Gradual loss of membrane-tethered VTCN1 from antigen-presenting cells combined with an increased release of soluble VTCN1 (sVTCN1) occurs in parallel to natural T1D development, potentiating hyperproliferation of diabetogenic T cells. Mechanistically, we demonstrate that the loss of membrane-tethered VTCN1 is linked to proteolytic cleavage mediated by the metalloproteinase nardilysin. The cleaved sVTCN1 fragment was detected at high levels in the peripheral blood of 53% T1D patients compared with only 9% of the healthy subjects. Elevated blood sVTCN1 levels appeared early in the disease progression and correlated with the aggressive pace of disease, highlighting the potential use of sVTCN1 as a new T1D biomarker, and identifying nardilysin as a potential therapeutic target. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Citation

Ilian A Radichev, Lilia V Maneva-Radicheva, Christina Amatya, Camille Parker, Jacob Ellefson, Clive Wasserfall, Mark Atkinson, Paul Burn, Alexei Y Savinov. Nardilysin-dependent proteolysis of cell-associated VTCN1 (B7-H4) marks type 1 diabetes development. Diabetes. 2014 Oct;63(10):3470-82

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PMID: 24848066

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