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

• Published in: Nature communications Vol. 9; no. 1; pp. 1136 - 13
• Main Authors: Liu, Junli, Huang, Xinfang, Hao, Shumeng, Wang, Yan, Liu, Manman, Xu, Jing, Zhang, Xingli, Yu, Tao, Gan, Shucheng, Dai, Dongfang, Luo, Xuan, Lu, Qingyan, Mao, Chaoming, Zhang, Yanyun, Shen, Nan, Li, Bin, Huang, Mingzhu, Zhu, Xiaodong, Jin, Jin, Cheng, Xuhong, Sun, Shao-Cong, Xiao, Yichuan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.03.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 13/51; 13/95; 631/250/2152/2153/1291; 631/250/38; 631/250/516/1909; 631/80/458/582; 82/1; 82/29; Adult; Animals; Autoantibodies; Autoimmune diseases; Autoimmunity; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Chronic conditions; Disease Models, Animal; Female; HEK293 Cells; Humanities and Social Sciences; Humans; Lupus; Lupus Erythematosus, Systemic - etiology; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - metabolism; Lymphocyte Activation; Lymphocytes B; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular modelling; multidisciplinary; NF-kappa B - metabolism; NF-kappaB-Inducing Kinase; NF-κB protein; Nuclear Proteins - deficiency; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Pathogenesis; Plasma cells; Protein Serine-Threonine Kinases - metabolism; Rodents; Science; Science (multidisciplinary); Signal Transduction; Signaling; Systemic lupus erythematosus; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - deficiency; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-03530-3

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. Systemic lupus erythematosus (SLE) is an autoimmune disorder mediated by excessive autoantibodies. Here the authors show that an E3 ubiquitin ligase, Peli1, negatively modulates noncanonical NF-κB signaling to restrain lupus-like symptoms in mice, and that Peli1 expression inversely correlates with SLE severity in humans.