The BH3-only protein BAD mediates TNFα cytotoxicity despite concurrent activation of IKK and NF-κB in septic shock.
The BH3-only protein BAD mediates TNFα cytotoxicity despite concurrent activation of IKK and NF-κB in septic shock.
复制标题
DOI：
10.1038/s41422-018-0041-7
复制
发表时间：
2018-07
期刊：
影响因子：
44.1
通讯作者：
Lin A
中科院分区：
文献类型：
--
作者：
Yan J;Zhang H;Xiang J;Zhao Y;Yuan X;Sun B;Lin A
炎性细胞因子TNFα在许多炎性和感染性疾病的病理学中起着至关重要的作用。然而，这些疾病中TNFα细胞毒性的潜在机制尚不完全清楚。在此我们报道了促凋亡BCL-2家族成员BAD介导TNFα的细胞毒性，尽管在体外通过诱导培养细胞的凋亡和在体内通过引起多器官的组织损伤和导致败血性休克的死亡率同时激活IKK和NF-κB。在高剂量下，TNFα通过激活Src-p190 GAP途径显著灭活RhoA，导致大量肌动蛋白应力纤维不稳定，随后大量BAD从细胞骨架释放到胞质溶胶。在这种情况下，激活的IKK不能磷酸化所有的胞质BAD，允许非磷酸化的BAD易位到线粒体，引发细胞凋亡。多种微生物感染利用与高剂量TNFα相同的机制来引起多个器官的细胞凋亡相关组织损伤。因此，Bad的丧失或BAD促凋亡活性的消除保护小鼠免受多个器官的组织损伤并降低死亡率。我们的研究结果支持了一个模型，在该模型中，尽管在培养的哺乳动物细胞和感染性休克中同时激活IKK-NF-κB通路，但BAD介导TNFα的细胞毒性。
The inflammatory cytokine TNFα plays a crucial role in the pathology of many inflammatory and infectious diseases. However, the mechanism underlying TNFα cytotoxicity in these diseases is incompletely understood. Here we report that the pro-apoptotic BCL-2 family member BAD mediates TNFα cytotoxicity despite concurrent activation of IKK and NF-κB in vitro by inducing apoptosis in cultured cells and in vivo by eliciting tissue damage of multiple organs and contributing to mortality in septic shock. At high doses, TNFα significantly inactivates RhoA through activation of the Src-p190GAP pathway, resulting in massive actin stress fiber destabilization, followed by substantial BAD release from the cytoskeleton to the cytosol. Under this condition, activated IKK fails to phosphorylate all cytosolic BAD, allowing translocation of non-phosphorylated BAD to mitochondria to trigger apoptosis. Polymicrobial infection utilizes the same mechanism as high-dose TNFα to elicit apoptosis-associated tissue damage of multiple organs. Consequently, loss of Bad or elimination of BAD pro-apoptotic activity protects mice from tissue damage of multiple organs and reduces mortality rates. Our results support a model in which BAD mediates TNFα cytotoxicity despite concurrent activation of the IKK-NF-κB pathway in cultured mammalian cells and in septic shock.
登录
查看更多内容
影响因子：
7.8
作者：
CHANG, JH;GILL, S;SETTLEMAN, J;PARSONS, SJ
通讯作者：
PARSONS, SJ
影响因子：
3.2
作者：
Guivier, Emmanuel;Galan, Maxime;Charbonnel, Nathalie
通讯作者：
Charbonnel, Nathalie
影响因子：
56.9
作者：
Bonni, A;Brunet, A;Greenberg, ME
通讯作者：
Greenberg, ME
影响因子：
64.8
作者：
De Smaele, E;Zazzeroni, F;Franzoso, G
通讯作者：
Franzoso, G
DOI：
10.1186/cc7966
发表时间：
2009
期刊：
Critical care (London, England)
影响因子：
--
作者：
Bantel H;Schulze-Osthoff K
通讯作者：
Schulze-Osthoff K