Aim2 Couples With Ube2i for Sumoylation-Mediated Repression of Interferon Signatures in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) involves kidney damage, and the inflammasome-caspase-1 axis has been demonstrated to promote renal pathogenesis. The present study was designed to explore the function of the Absent in Melanoma 2 (Aim2) protein in SLE.

Female wild-type Aim2^-/- , Aim2^-/- Ifnar1^-/- , Aim2^-/- Rag1^-/- , and Asc^-/- mice ages 8-10 weeks received 1 intraperitoneal injection of 500 μl pristane or saline, and survival of mice was monitored twice a week for 6 months.

The absence of Aim2, but not Asc, led to enhanced SLE in mice that received pristane treatment. Increased immune cell infiltration and type I interferon (IFN) signatures in the kidneys of Aim2^-/- mice coincided with severity of lupus, 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 to control animals. Accordingly, transcriptome analysis revealed that Aim2 deficiency led to enhanced expression of type I IFN-induced genes in the kidneys even at an early developmental stage. Mechanistically, Aim2 bound ubiquitin-conjugating enzyme 2i (Ube2i), which mediates sumoylation-based suppression of type I IFN expression deficiency of Aim2 decreased cellular sumoylation, resulting in an augmented type I IFN signature and kidney pathogenesis.

The present study demonstrates a critical role for Aim2 in an optimal Ube2i-mediated sumoylation-based suppression of type I IFN generation and development of SLE. As such, the Aim2-Ube2i axis can thus be a novel target for intervention in SLE.