Glycans and glycosylation defects as novel targets in lupus
This project focuses on a novel function of TREX1/DNase III, a mammalian endoplasmic reticulum (ER)-associated DNase, and its therapeutic translation. We recently found that TREX1 regulates the ER-associated oligosaccharyltransferase (OST) complex to suppress free glycans release and glycosylation defects. Our discovery revealed an important connection between dysregulation of a classical glycotransferase and autoimmune diseases. In this proposal, we will use TREX1 frame-shift SLE and RVCL patients and a knock-in mouse model carrying the same mutation to further dissect the disease mechanism in vivo. We hope to identify novel glycans, glycosylation defects and autoantibodies that can serve as biomarkers, as well as mechanisms by which OST dysregulation cause autoimmunity. We will also examine an OST inhibitor in patient cells and the knock-in mice to establish preclinical evidence for treating TREX1 frame-shift associated diseases. The glycans and glycosylation defects identified from the TREX1 model will also be applied to general SLEs through a small-scale screen, as a first step towards identifying a biomarker for selecting SLE cases that may benefit from treatments targeted to correct glycosylation defects.