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FLASH coordinates NF-kappa B activity via TRAF2. FLASH 通过 TRAF2 协调 NF-kappa B 的活动。

Lontar Komputer

Pub Date : 2001-07-06 Epub Date: 2001-05-04 DOI: 10.1074/jbc.M102941200

Y H Choi, K B Kim, H H Kim, G S Hong, Y K Kwon, C W Chung, Y M Park, Z J Shen, B J Kim, S Y Lee, Y K Jung

FLASH is a protein recently shown to interact with the death effector domain of caspase-8 and is likely to be a component of the death-inducing signaling complex in receptor-mediated apoptosis. Here we show that antisense oligonucleotide-induced inhibition of FLASH expression abolished TNF-alpha-induced activation of NF-kappaB in HEK293 cells, as determined by luciferase reporter gene expression driven by a NF-kappaB responsive promoter. Conversely, overexpression of FLASH dose-dependently activated NF-kappaB, an effect suppressed by dominant negative mutants of TRAF2, NIK, and IKKalpha, and partially by those of TRAF5 and TRAF6. TRAF2 was co-immunoprecipitated with FLASH from the cell extracts of HEK293 cells or HeLa cells stably expressing exogenous FLASH (HeLa/HA-FLASH). Furthermore, serial deletion mapping demonstrated that a domain spanning the residues 856-1191 of FLASH activated NF-kappaB as efficiently as the full-length and could directly bind to TRAF2 in vitro and in the transfected cells. Taken together, these results suggest that FLASH coordinates downstream NF-kappaB activity via a TRAF2-dependent pathway in the TNF-alpha signaling.

FLASH是一种最近被证明能与caspase-8的死亡效应结构域相互作用的蛋白质，很可能是受体介导的细胞凋亡中死亡诱导信号复合体的一个组成部分。在这里，我们发现反义寡核苷酸诱导的FLASH表达抑制可取消TNF-α诱导的NF-kappaB在HEK293细胞中的激活，这是由NF-kappaB响应启动子驱动的荧光素酶报告基因表达所确定的。相反，FLASH 的过表达剂量依赖性地激活了 NF-kappaB，这种效应被 TRAF2、NIK 和 IKKalpha 的显性负突变体所抑制，部分被 TRAF5 和 TRAF6 的显性负突变体所抑制。在 HEK293 细胞或稳定表达外源 FLASH 的 HeLa 细胞（HeLa/HA-FLASH）的细胞提取物中，TRAF2 与 FLASH 被共免疫沉淀。此外，序列缺失图谱显示，跨越 FLASH 的 856-1191 残基的结构域与全长结构域一样有效地激活了 NF-kappaB，并能在体外和转染细胞中直接与 TRAF2 结合。综上所述，这些结果表明，在 TNF-α 信号转导过程中，FLASH 通过 TRAF2 依赖性途径协调下游 NF-kappaB 的活性。

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