Journal
IMMUNITY
Volume 43, Issue 3, Pages 463-474Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2015.07.022
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Funding
- Washington University Protein Production and Purification Core Facility of the Rheumatic Disease Core Center [P30 AR048335]
- UT Southwestern
- Biomedical Science from UT Southwestern
- US NIH [AI098569, AR067135, GM038545, AR048335]
- Alliance for Lupus Foundation
- Welch Foundation
- NSF
- Cure CRV Research, Energy 4 A Cure Foundation
- Clayco Corporation
- Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases
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TREX1 is an endoplasmic reticulum (ER)-associated negative regulator of innate immunity. TREX1 mutations are associated with autoimmune and autoinflammatory diseases. Biallelic mutations abrogating DNase activity cause autoimmunity by allowing immunogenic self-DNA to accumulate, but it is unknown how dominant frameshift (fs) mutations that encode DNase-active but mislocalized proteins cause disease. We found that the TREX1 C terminus suppressed immune activation by interacting with the ER oligosaccharyltransferase (OST) complex and stabilizing its catalytic integrity. C-terminal truncation of TREX1 by fs mutations dysregulated the OST complex, leading to free glycan release from dolichol carriers, as well as immune activation and autoantibody production. A connection between OST dysregulation and immune disorders was demonstrated in Trex1(-/-) mice, TREX1-V235fs patient lymphoblasts, and TREX1-V235fs knock-in mice. Inhibiting OST with aclacinomycin corrects the glycan and immune defects associated with Trex1 deficiency or fs mutation. This function of the TREX1 C terminus suggests a potential therapeutic option for TREX1-fs mutant-associated diseases.
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