Abstract
Systemic lupus erythematosus (SLE) is characterized by uncontrolled secretion of autoantibodies by plasma cells. Although the functional importance of plasma cells and autoantibodies 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-κB signaling. Mechanically, Peli1 functions as an E3 ligase to associate with NF-κB inducing kinase (NIK) and mediates NIK Lys48 ubiquitination and degradation. Overexpression of Peli1 inhibits noncanonical NF-κB 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-κB pathway in the context of restraining the pathogenesis of lupus-like disease.
Highlights
Systemic lupus erythematosus (SLE) is characterized by uncontrolled secretion of autoantibodies by plasma cells
We previously reported and confirmed that Peli[1] deficiency is dispensable for BCR-induced but impaired TLRinduced B cell proliferation[27] (Supplementary Fig. 1c), which promote us to speculate that the incensement of B cells in Peli1deficient mice may attribute to the promotion of noncanonical NF-κB signaling
To figure out whether and how Peli[1] mediate the inhibition of noncanonical NF-κB activation, we firstly examined the surface expression of CD40 and BAFF receptor (BAFFR), which are the two major receptors responsible for the transduction of noncanonical NF-κB signaling in B cells
Summary
Systemic lupus erythematosus (SLE) is characterized by uncontrolled secretion of autoantibodies by plasma cells. Peli[1] functions as an E3 ligase to associate with NF-κB inducing kinase (NIK) and mediates NIK Lys[48] ubiquitination and degradation. Overexpression of Peli[1] inhibits noncanonical NF-κB activation and alleviates lupus-like disease. Our findings establish Peli[1] as a negative regulator of the noncanonical NF-κB pathway in the context of restraining the pathogenesis of lupus-like disease. Mice overexpressing BAFF (BAFF-Tg mice) exhibit hyperactivation of noncanonical pathway and develop an autoimmune lupus-like disease with increasing production of autoantibodies[20,21,22]. We provide molecular and genetic evidence that Peli[1] serves as an E3 ubiquitin ligase of NIK, regulating Lys48-linked ubiquitination of NIK and noncanonical NF-κB activation
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