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E3 ligase FBXW7 aggravates TMPD-induced systemic lupus erythematosus by promoting cell apoptosis

Cellular & Molecular Immunology volume 15, pages 1057–1070 (2018)Cite this article

Abstract

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease, and the pathogenesis of SLE has not been fully elucidated. The E3 ubiquitin ligase FBXW7 has been well characterized in cancer as a tumor suppressor that can promote the ubiquitination and subsequent degradation of various oncoproteins; however, the potential role of FBXW7 in autoimmune diseases is unclear. In the present study, we identified that FBXW7 is a crucial exacerbating factor for SLE development and progression in a mouse model induced by 2, 6, 10, 14-tetramethylpentadecane (TMPD). Myeloid cell-specific FBXW7-deficient (Lysm+FBXW7f/f) C57BL/6 mice showed decreased immune complex accumulation, glomerulonephritis, glomerular mesangial cell proliferation, and base-membrane thickness in the kidney. Lysm+FBXW7f/f mice produced fewer anti-Sm/RNP and anti-ANA autoantibodies and showed a decreased MHC II expression in B cells. In Lysm+FBXW7f/f mice, we observed that cell apoptosis was reduced and that fewer CD11b+Ly6Chi inflammatory monocytes were recruited to the peritoneal cavity. Consistently, diffuse pulmonary hemorrhage (DPH) was also decreased in Lysm+FBXW7f/f mice. Mechanistically, we clarified that FBXW7 promoted TMPD-induced cell apoptosis by catalyzing MCL1 degradation through K48-linked ubiquitination. Our work revealed that FBXW7 expression in myeloid cells played a crucial role in TMPD-induced SLE progression in mice, which may provide novel ideas and theoretical support for understanding the pathogenesis of SLE.

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Acknowledgements

We would like to thank Prof. Ximei Wu for providing the Lysm-Cre mice and Prof. Hong Deng for the kidney pathology analysis. This work was supported by the National Natural Science Foundation of China (81771699, 31870907, and 81571524), Natural Science Foundation of Zhejiang Province (Z19H100001), and National Key Basic Research Program of China (2014CB542101).

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  1. These authors contributed equally: Zhenlu Chong, Chunjing Bao

Authors and Affiliations

  1. Institute of Immunology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, China

    Zhenlu Chong, Chunjing Bao, Jia He, Tianxiao Chen, Gaopeng Li, Huanle Li, Lutong Fang, Yinjing Song, Lihua Lai, Yang Liu & Qingqing Wang

  2. The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China

    Lijia Zhong

  3. Sir Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China

    Guoxiang Fu

  4. Department of Rheumatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China

    Xuyan Yang

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Chong, Z., Bao, C., He, J. et al. E3 ligase FBXW7 aggravates TMPD-induced systemic lupus erythematosus by promoting cell apoptosis. Cell Mol Immunol 15, 1057–1070 (2018). https://doi.org/10.1038/s41423-018-0167-z

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