The SLE‐associated TREX1‐P212fs mutation disrupts ER association leading to type I interferonopathy

Abstract The TREX1 gene encodes a highly efficient DNA exonuclease that plays an important role in maintaining DNA homeostasis in the cytoplasm. TREX1 mutations lead to a spectrum of type I interferonopathies that are characterized by systemic inflammation, high blood levels of autoantibodies, and spontaneously activated immunity. The TREX1‐P212fs mutation is thought to be linked to systemic lupus erythematosus (SLE). Here, we analyzed the functions of 20 TREX1 mutants and found that the TREX1‐P212fs mutant was able to reduce DNA enzyme activity and missed endoplasmic reticulum localization. Mouse‐derived in situ Trex1 models of transcoding mutations have not been reported. We successfully constructed Trex1‐P212fs mice by CRISPR‐Cas9 technology. Trex1 P212fs/P212fs mice exhibit systemic inflammation, lymphocytosis, vasculitis, and kidney disease. The excessive autoantibody production was also present in these mice. We further demonstrated that TREX1 (1–212) protein lost its interaction with RPN1, the subunit that makes up the oligosaccharyl transferase (OST) complex. These data suggest an important role of TREX1‐C‐terminal association with the endoplasmic reticulum in inducing immune activation and the Trex1‐P212fs model may provide theoretical support for a better understanding of SLE treatment and defense.