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Nature:膜蛋白FasL促进细胞凋亡的途径

来源:未知 编辑:admin 发布时间:2017-08-14
Nature:膜蛋白FasL促进细胞凋亡的途径

名为FasL (Fas ligand)的跨膜蛋白是在免疫调控中有重要作用的肿瘤坏死因子家族中的一员。FasL与其受体的结合诱导细胞凋亡,但尚不清楚细胞死亡对fasL的细胞功能有多重要。用剔除相关基因的突变小鼠(它们缺失分泌的FasL、但却表达正常水平的与膜结合的FasL;或者缺失与膜结合的FasL、但却仍能产生分泌的FasL)所做实验表明,可溶FasL通过不涉及细胞凋亡的机制促进自体免疫和肿瘤形成。

原文摘要:

membrane-bound Fas ligand only is essential for Fas-induced apoptosis

Fas ligand (FasL), an apoptosis-inducing member of the TNF cytokine family, and its receptor Fas are critical for the shutdown of chronic immune responses1, 2, 3 and prevention of autoimmunity4, 5. Accordingly, mutations in their genes cause severe lymphadenopathy and autoimmune disease in mice6, 7 and humans8, 9. FasL function is regulated by deposition in the plasma membrane and metalloprotease-mediated shedding10, 11. Here we generated gene-targeted mice that selectively lack either secreted FasL (sFasL) or membrane-bound FasL (mFasL) to resolve which of these forms is required for cell killing and to explore their hypothesized non-apoptotic activities. Mice lacking sFasL (FasLs/s) appeared normal and their T cells readily killed target cells, whereas T cells lacking mFasL (FasLm/m) could not kill cells through Fas activation. FasLm/m mice developed lymphadenopathy and hyper-gammaglobulinaemia, similar to FasLgld/gld mice, which express a mutant form of FasL that cannot bind Fas, but surprisingly, FasLm/m mice (on a C57BL/6 background) succumbed to systemic lupus erythematosus (SLE)-like autoimmune kidney destruction and histiocytic sarcoma, diseases that occur only rarely and much later in FasLgld/gld mice. These results demonstrate that mFasL is essential for cytotoxic activity and constitutes the guardian against lymphadenopathy, autoimmunity and cancer, whereas excess sFasL appears to promote autoimmunity and tumorigenesis through non-apoptotic activities.

作者:weiyanjie 点击:

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