I-05 Dual functions of TREX1 in autoimmune diseases

Abstract

Background TREX1 is an endoplasmic reticulum (ER)-associated exonuclease and a critical negative regulator of innate immunity. TREX1 mutations are associated with several autoimmune and autoinflammatory diseases, including Aicardi–Goutieres syndrome (AGS), familial chilblain lupus, systemic lupus erythematosus (SLE), and retinal vasculopathy with cerebral leukodystrophy (RVCL). Both DNase-dependent and –independent functions have been described for TREX1 N-terminal DNase domain and C-terminal ER localization domain, respectively. Biallelic mutations abrogating DNase activity cause autoimmunity by allowing immunogenic self-DNA to activate the cGAS-STING-TBK1 signalling pathway leading to type I interferon (IFN) response and autoimmunity. Methods and results We recently showed that inhibiting TBK1 by a potent small molecule inhibitor, Compound II, was able to ameliorate autoimmune disease phenotypes of Trex1-/- mice, increase mouse survival, and dampen the IFN gene signature in TREX1 mutant patient lymphoblasts. We are also interested in a group of dominant frame-shift (fs) mutations that encode DNase-active but mislocalized proteins. We found that TREX1 C-terminus suppressed immune activation by interacting with the ER oligosaccharyltransferase (OST) complex and stabilising its catalytic integrity. C-terminal truncation of TREX1 by fs mutations dysregulated the OST complex, leading to free glycan release, immune activation and autoantibody production. Proper glycosylation of proteins in immunity is critical for their function, and protein glycosylation is also important for preventing self-immune recognition and production of autoantibodies. We recently established the TREX1-V235fs knock-in mouse to better understand the disease associated with TREX1-fs mutations. Conclusion Together, our past and ongoing studies reveal dual functions of TREX1 in regulating self-DNA and self-glycan metabolism, and suggest potential therapeutic targets and options for TREX1 mutant-associated autoimmune diseases.