Aim2 Couples with Ube2i for Sumoylation-mediated Repression of Interferon Signatures in Systemic Lupus Erythematosus.

OBJECTIVE Systemic lupus erythematosus (SLE) involves kidney damage, and the inflammasome-caspase-1 axis had been demonstrated to promote renal pathogenesis. The current study was designed to explore the function of Aim2 in SLE. METHODS Female WT, Aim2-/- , Aim2-/- Ifnar1-/- , Aim2-/- Rag1-/- , and Asc-/- mice at 8-10 weeks of age received one intraperitoneal injection of 500μl pristane or saline, and survival was monitored twice a week for 6 months. RESULTS The absence of Aim2 but not Asc led to enhanced SLE in pristane-injected mice. Increased immune cell infiltration and type I interferon (IFN-I) signatures in the kidneys of Aim2-/- mice coincided with lupus severity, which was alleviated by blockade of Ifnar1-mediated signal. Adaptive immune cells were also involved in the glomerular lesions of Aim2-/- mice after pristane challenge. Importantly, even in the absence of pristane, plasmacytoid dendritic cells in the kidneys of Aim2-/- mice were significantly increased compared with control animals. Accordingly, transcriptome analysis revealed that Aim2 deficiency led to enhanced expression of IFN-I-induced genes in the kidney even at an early developmental stage. Mechanistically, Aim2 bound Ube2i, which mediates sumoylation-based suppression of IFN-I expression; deficiency of Aim2 decreased cellular sumoylation, resulting in an augmented IFN-I signature and kidney pathogenesis. CONCLUSION This study demonstrates a critical role for Aim2 in an optimal Ube2i-mediated sumoylation-based suppression of IFN-I generation and development of SLE, the Aim2-Ube2i axis can thus be a novel target for intervention.