Department of Biochemistry, La Trobe University, Kingsbury Drive, Melbourne, Victoria 3086, Australia.
Cell Death Differ. 2010 Mar;17(3):482-7. doi: 10.1038/cdd.2009.178. Epub 2009 Nov 20.
On TNF binding, receptor-interacting protein kinase 1 (RIPK1) is recruited to the cytoplasmic domain of TNFR1, at which it becomes ubiquitylated and serves as a platform for recruitment and activation of NEMO/IKK1/IKK2 and TAK1/TAB2. RIPK1 is commonly thought to be required for the activation of canonical NF-kappaB and for inhibition TNFR1-induced apoptosis. RIPK1 has, however, also been reported to be essential for TNFR1-induced apoptosis when cIAPs are depleted. To determine the role of RIPK1 in TNF/IAP antagonist-induced death, we compared wild type (WT) and RIPK1(-/-) mouse embryonic fibroblasts (MEFs) treated with these compounds. On being treated with TNF plus IAP antagonist, RIPK1(-/-) MEFs survived, unlike WT MEFs, demonstrating a killing activity of RIPK1. Surprisingly, however, on being treated with TNF alone, RIPK1(-/-) MEFs activated canonical NF-kappaB and did not die. Furthermore, several cell types from E18 RIPK1(-/-) embryos seem to activate NF-kappaB in response to TNF. These data indicate that models proposing that RIPK1 is essential for TNFR1 to activate canonical NF-kappaB are incorrect.
在与 TNF 结合时，受体相互作用蛋白激酶 1（RIPK1）被招募到 TNFR1 的细胞质结构域，在那里它被泛素化，并作为募集和激活 NEMO/IKK1/IKK2 和 TAK1/TAB2 的平台。通常认为 RIPK1 对于经典 NF-κB 的激活以及抑制 TNFR1 诱导的细胞凋亡是必需的。然而，当 cIAPs 被耗尽时，RIPK1 也被报道对于 TNFR1 诱导的细胞凋亡是必需的。为了确定 RIPK1 在 TNF/IAP 拮抗剂诱导的死亡中的作用，我们比较了用这些化合物处理的野生型（WT）和 RIPK1（-/-）小鼠胚胎成纤维细胞（MEFs）。在用 TNF 加 IAP 拮抗剂处理后，RIPK1（-/-）MEFs 存活下来，与 WT MEFs 不同，这表明 RIPK1 具有杀伤活性。然而，令人惊讶的是，在用 TNF 单独处理时，RIPK1（-/-）MEFs 激活了经典 NF-κB，并没有死亡。此外，来自 E18 RIPK1（-/-）胚胎的几种细胞类型似乎对 TNF 有反应而激活 NF-κB。这些数据表明，提出 RIPK1 对于 TNFR1 激活经典 NF-κB 是必需的模型是不正确的。
