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

Junli Liu, Xinfang Huang, Shumeng Hao, Yan Wang, Manman Liu, Jing Xu, Xingli Zhang, Tao Yu, Shucheng Gan, Dongfang Dai, Xuan Luo, Qingyan Lu, Chaoming Mao, Yanyun Zhang, Nan Shen, Bin Li, Mingzhu Huang, Xiaodong Zhu, Jin Jin, Xuhong Cheng, Shao-Cong Sun and Yichuan Xiao ()
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Junli Liu: University of Chinese Academy of Sciences
Xinfang Huang: Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Shumeng Hao: University of Chinese Academy of Sciences
Yan Wang: University of Chinese Academy of Sciences
Manman Liu: Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Jing Xu: University of Chinese Academy of Sciences
Xingli Zhang: University of Chinese Academy of Sciences
Tao Yu: University of Chinese Academy of Sciences
Shucheng Gan: University of Chinese Academy of Sciences
Dongfang Dai: The Affiliated Hospital of Jiangsu University
Xuan Luo: The Affiliated Hospital of Jiangsu University
Qingyan Lu: The Affiliated Hospital of Jiangsu University
Chaoming Mao: The Affiliated Hospital of Jiangsu University
Yanyun Zhang: University of Chinese Academy of Sciences
Nan Shen: University of Chinese Academy of Sciences
Bin Li: Shanghai Jiao Tong University School of Medicine
Mingzhu Huang: Fudan University Shanghai Cancer Center
Xiaodong Zhu: Fudan University Shanghai Cancer Center
Jin Jin: Zhejiang University
Xuhong Cheng: The University of Texas
Shao-Cong Sun: The University of Texas
Yichuan Xiao: University of Chinese Academy of Sciences

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03530-3

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