期刊
CELLULAR & MOLECULAR IMMUNOLOGY
卷 15, 期 12, 页码 1057-1070出版社
CHIN SOCIETY IMMUNOLOGY
DOI: 10.1038/s41423-018-0167-z
关键词
Systemic lupus erythematosus; apoptosis; FBXW7; MCL1; ubiquitination
类别
资金
- National Natural Science Foundation of China [81771699, 31870907, 81571524]
- Natural Science Foundation of Zhejiang Province [Z19H100001]
- National Key Basic Research Program of China [2014CB542101]
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据