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

Cellular & molecular immunology (2018-10-03)
Zhenlu Chong, Chunjing Bao, Jia He, Tianxiao Chen, Lijia Zhong, Gaopeng Li, Huanle Li, Lutong Fang, Yinjing Song, Guoxiang Fu, Xuyan Yang, Lihua Lai, Yang Liu, Qingqing Wang
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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Sigma-Aldrich
Pristane, synthetic, ≥98% (GC)