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

• Published in: Cellular & molecular immunology Vol. 15; no. 12; pp. 1057 - 1070
• Main Authors: Chong, Zhenlu, Bao, Chunjing, He, Jia, Chen, Tianxiao, Zhong, Lijia, Li, Gaopeng, Li, Huanle, Fang, Lutong, Song, Yinjing, Fu, Guoxiang, Yang, Xuyan, Lai, Lihua, Liu, Yang, Wang, Qingqing
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2018; Nature Publishing Group
• Subjects: Antibodies; Apoptosis; Autoantibodies; Autoimmune diseases; Biomedical and Life Sciences; Biomedicine; Cancer; CD11b antigen; Cdc4 protein; Cell proliferation; Glomerulonephritis; Hemorrhage; Immunology; Inflammation; Kidneys; Lupus; Lymphocytes B; Major histocompatibility complex; Mcl-1 protein; Medical Microbiology; Microbiology; Monocytes; Myeloid cells; Pathogenesis; Peritoneum; Systemic lupus erythematosus; Tumor suppressor genes; Ubiquitin; Ubiquitin-protein ligase; Ubiquitination; Vaccine; apoptosis; Systemic lupus erythematosus; ubiquitination; MCL1; FBXW7
• ISSN: 1672-7681; 2042-0226; 2042-0226
• DOI: 10.1038/s41423-018-0167-z

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 + FBXW7 f/f ) C57BL/6 mice showed decreased immune complex accumulation, glomerulonephritis, glomerular mesangial cell proliferation, and base-membrane thickness in the kidney. Lysm + FBXW7 f/f mice produced fewer anti-Sm/RNP and anti-ANA autoantibodies and showed a decreased MHC II expression in B cells. In Lysm + FBXW7 f/f mice, we observed that cell apoptosis was reduced and that fewer CD11b + Ly6C hi inflammatory monocytes were recruited to the peritoneal cavity. Consistently, diffuse pulmonary hemorrhage (DPH) was also decreased in Lysm + FBXW7 f/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.