Immunology Institute, Mount Sinai School of Medicine, New York, New York, United States of America.
PLoS One. 2012;7(7):e41238. doi: 10.1371/journal.pone.0041238. Epub 2012 Jul 26.
TNF can trigger two opposing responses: cell survival and cell death. TNFR1 activates caspases that orchestrate apoptosis but some cell types switch to a necrotic death when treated with caspase inhibitors. Several genes that are required to orchestrate cell death by programmed necrosis have been identified, such as the kinase RIP1, but very little is known about the inhibitory signals that keep this necrotic cell death pathway in check. We demonstrate that T cells lacking the regulatory subunit of IKK, NFκB essential modifier (NEMO), are hypersensitive to programmed necrosis when stimulated with TNF in the presence of caspase inhibitors. Surprisingly, this pro-survival activity of NEMO is independent of NFκB-mediated gene transcription. Instead, NEMO inhibits necrosis by binding to ubiquitinated RIP1 to restrain RIP1 from engaging the necrotic death pathway. In the absence of NEMO, or if ubiquitination of RIP1 is blocked, necrosis ensues when caspases are blocked. These results indicate that recruitment of NEMO to ubiquitinated RIP1 is a key step in the TNFR1 signaling pathway that determines whether RIP1 triggers a necrotic death response.
肿瘤坏死因子（TNF）可引发两种相反的反应：细胞存活和细胞死亡。TNFR1 可激活细胞凋亡的胱天蛋白酶，但某些细胞类型在用胱天蛋白酶抑制剂处理时会转向坏死性死亡。已经鉴定出了一些需要通过程序性坏死来协调细胞死亡的基因，例如激酶 RIP1，但对于抑制信号通路保持这种坏死性细胞死亡途径的抑制信号知之甚少。我们证明，在存在胱天蛋白酶抑制剂的情况下，用 TNF 刺激时，缺乏 IKK 调节亚基 NFκB 必需修饰物（NEMO）的 T 细胞对程序性坏死变得敏感。令人惊讶的是，NEMO 的这种促生存活性不依赖于 NFκB 介导的基因转录。相反，NEMO 通过与泛素化的 RIP1 结合来抑制 RIP1 参与坏死性死亡途径，从而抑制坏死。在缺乏 NEMO 的情况下，或者如果 RIP1 的泛素化被阻断，则在阻断胱天蛋白酶时会发生坏死。这些结果表明，NEMO 募集到泛素化的 RIP1 是 TNFR1 信号通路中的一个关键步骤，决定了 RIP1 是否引发坏死性死亡反应。
