E3 ligase FBXW7 aggravates TMPD-induced systemic lupus erythematosus by promoting cell apoptosis
E3 ligase FBXW7 aggravates TMPD-induced systemic lupus erythematosus by promoting cell apoptosis
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E3连接酶FBXW7通过促进细胞凋亡加重TMPD诱导的系统性红斑狼疮
DOI：
10.1038/s41423-018-0167-z
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发表时间：
2018-12-01
影响因子：
24.1
通讯作者：
Wang，Qingqing
中科院分区：
文献类型：
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作者：
Chong，Zhenlu;Bao，Chunjing;Wang，Qingqing
系统性红斑狼疮（SLE）是一种全身性自身免疫性疾病，其发病机制尚未完全阐明。E3泛素连接酶FBXW 7在癌症中被很好地表征为肿瘤抑制因子，其可以促进各种癌蛋白的泛素化和随后的降解;然而，FBXW 7在自身免疫性疾病中的潜在作用尚不清楚。在本研究中，我们在由2，6，10，14-四甲基十五烷（TMPD）诱导的小鼠模型中鉴定了FBXW 7是SLE发展和进展的关键加重因子。骨髓细胞特异性FBXW 7缺陷型（Lysm+ FBXW 7 f/f）C57 BL/6小鼠表现出肾脏中免疫复合物蓄积、肾小球肾炎、肾小球系膜细胞增殖和基底膜厚度降低。Lysm+ FBXW 7 f/f小鼠产生的抗Sm/RNP和抗ANA自身抗体较少，并且显示B细胞中MHC II表达减少。在Lysm+ FBXW 7 f/f小鼠中，我们观察到细胞凋亡减少，并且更少的CD 11b + Ly 6Chi炎性单核细胞被募集到腹膜腔。同时，Lysm+ FBXW 7 f/f小鼠的弥漫性肺出血（DPH）也减少。从机制上讲，我们阐明了FBXW 7通过K48连接的泛素化催化MCL 1降解促进TMPD诱导的细胞凋亡。本研究揭示了FBXW 7在髓系细胞中的表达在TMPD诱导的小鼠SLE进展中起着至关重要的作用，这可能为理解SLE的发病机制提供新的思路和理论支持。
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/fmice produced fewer anti-Sm/RNP and anti-ANA autoantibodies and showed a decreased MHC II expression in B cells. In Lysm+FBXW7f/fmice, we observed that cell apoptosis was reduced and that fewer CD11b+Ly6Chiinflammatory monocytes were recruited to the peritoneal cavity. Consistently, diffuse pulmonary hemorrhage (DPH) was also decreased in Lysm+FBXW7f/fmice. 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.