Peli1 negatively regulates noncanonical NF-κB signaling to restrain systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is characterized by uncontrolled secretion of auto-antibodies by plasma cells. Although the functional importance of plasma cells and auto-antibodies in SLE has been well established, the underlying molecular mechanisms of controlling autoantibody production remain poorly understood. Here we show that Peli1 has a B cell-intrinsic function to protect against lupus-like autoimmunity in mice. Peli1 deficiency in B cells induces autoantibody production via noncanonical NF-kappa B signaling. Mechanically, Peli1 functions as an E3 ligase to associate with NF-kappa B inducing kinase (NIK) and mediates NIK Lys48 ubiquitination and degradation. Overexpression of Peli1 inhibits noncanonical NF-kappa B activation and alleviates lupus-like disease. In humans, PELI1 levels negatively correlate with disease severity in SLE patients. Our findings establish Peli1 as a negative regulator of the noncanonical NF-kappa B pathway in the context of restraining the pathogenesis of lupus-like disease.