Defective CD95/APO-1/Fas signal complex formation in the human autoimmune lymphoproliferative syndrome, type Ia
Defective CD95/APO-1/Fas signal complex formation in the human autoimmune lymphoproliferative syndrome, type Ia
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DOI：
10.1073/pnas.96.8.4552
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发表时间：
1999-04-13
影响因子：
11.1
通讯作者：
Lenardo, MJ
中科院分区：
文献类型：
--
作者：
Martin, DA;Zheng, LX;Lenardo, MJ
CD95(APO-1/Fas)受体杂合突变存在于大多数自身免疫性淋巴增殖性综合征(ALPS)患者中，并以一种未知的机制主要干扰细胞的凋亡。我们发现，9个独立的Alps CD95死亡区域突变导致细胞质死亡区域结构的局部或整体变化，导致无法结合FADD/MORT1信号蛋白。尽管异常等位基因存在杂合性，但阿尔卑斯病患者淋巴细胞的FADD关联性显著降低，CD95交联后caspase募集和激活丢失。这些数据表明，阿尔卑斯山的胞浆内CD95突变主要通过破坏死亡结构域与信号蛋白FADD/MORT1的相互作用来损害细胞凋亡。
Heterozygous mutations in the CD95 (APO-1/Fas) receptor occur in most individuals with autoimmune lymphoproliferative syndrome (ALPS) and dominantly interfere with apoptosis by an unknown mechanism. We show that local or global alterations in the structure of the cytoplasmic death domain from nine independent ALPS CD95 death-domain mutations result in a: failure to bind the FADD/MORT1 signaling protein. Despite heterozygosity for the abnormal allele, lymphocytes from ALPS patients showed markedly decreased FADD association and a loss of caspase recruitment and activation after CD95 crosslinking. These data suggest that intracytoplasmic CD95 mutations in ALPS impair apoptosis chiefly by disrupting death-domain interactions with the signaling protein FADD/MORT1.