Keratin attenuates tumor necrosis factor-induced cytotoxicity through association with TRADD.
Keratin attenuates tumor necrosis factor-induced cytotoxicity through association with TRADD.
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DOI：
10.1083/jcb.200103078
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发表时间：
2001-10-29
期刊：
影响因子：
--
通讯作者：
Inagaki M
中科院分区：
文献类型：
--
作者：
Inada H;Izawa I;Nishizawa M;Fujita E;Kiyono T;Takahashi T;Momoi T;Inagaki M
角蛋白8和18 （K8/18）是单层或单层上皮中中间丝蛋白（IF）的主要成分。最近的数据显示，缺乏K8/18的正常和恶性上皮细胞对肿瘤坏死因子（TNF）诱导的细胞死亡的敏感性高出近100倍。我们现在已经确定人类TNF受体1型（TNFR1）相关死亡结构域蛋白（TRADD）是k18相互作用蛋白。在双杂交系统中测试的IF蛋白中，TRADD特异性结合I型（酸性）角蛋白K18和K14。TRADD的cooh末端区域与K18的棒状结构域的线圈Ia相互作用。在人乳腺上皮细胞中，内源性TRADD与K18共免疫沉淀，并与K8/18纤维共定位。在缺乏角蛋白的SW13细胞中，含有tradd结合域的K18的NH2末端（氨基酸1-270）的过表达以及K8/18的过表达使细胞更能抵抗TNF的杀伤。我们还发现，在SW13细胞中，K18和K8/18的NH2末端过表达与内源性TRADD相关，从而抑制caspase-8的激活。这些结果表明，K18可能会隔离TRADD，以减弱TRADD与活化的TNFR1之间的相互作用，并减缓tnf诱导的简单上皮细胞凋亡。
Keratin 8 and 18 (K8/18) are the major components of intermediate filament (IF) proteins of simple or single-layered epithelia. Recent data show that normal and malignant epithelial cells deficient in K8/18 are nearly 100 times more sensitive to tumor necrosis factor (TNF)–induced cell death. We have now identified human TNF receptor type 1 (TNFR1)–associated death domain protein (TRADD) to be the K18-interacting protein. Among IF proteins tested in two-hybrid systems, TRADD specifically bound K18 and K14, type I (acidic) keratins. The COOH-terminal region of TRADD interacted with the coil Ia of the rod domain of K18. Endogenous TRADD coimmunoprecipitated with K18, and colocalized with K8/18 filaments in human mammary epithelial cells. Overexpression of the NH2 terminus (amino acids 1–270) of K18 containing the TRADD-binding domain as well as overexpression of K8/18 in SW13 cells, which are devoid of keratins, rendered the cells more resistant to killing by TNF. We also showed that overexpressed NH2 termini of K18 and K8/18 were associated with endogenous TRADD in SW13 cells, resulting in the inhibition of caspase-8 activation. These results indicate that K18 may sequester TRADD to attenuate interactions between TRADD and activated TNFR1 and moderate TNF-induced apoptosis in simple epithelial cells.
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DOI：
10.1083/jcb.149.5.999
发表时间：
2000-05-29
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kaufman CK;Fuchs E
通讯作者：
Fuchs E
影响因子：
16
作者：
Dong, CM;Li, ZR;Goldschmidt-Clermont, PJ
通讯作者：
Goldschmidt-Clermont, PJ
影响因子：
64.5
作者：
HSU, HL;XIONG, J;GOEDDEL, DV
通讯作者：
GOEDDEL, DV
影响因子：
11.4
作者：
Medema, JP;Scaffidi, C;Peter, ME
通讯作者：
Peter, ME
影响因子：
64.5
作者：
Boldin, MP;Goncharov, TM;Wallach, D
通讯作者：
Wallach, D