Department of Biological Sciences, Chungnam National University, Yuseong-gu, Daejeon 305-764, South Korea.
Graduate School of New Drug Discovery and Development, Chungnam National University, Yuseong-gu, Daejeon 305-764, South Korea.
Biochim Biophys Acta Mol Cell Res. 2018 Jan;1865(1):132-141. doi: 10.1016/j.bbamcr.2017.10.004. Epub 2017 Oct 7.
Regulated necrosis occurs in various pathophysiological conditions under oxidative stress. Here, we report that receptor-interacting protein kinase 1 (RIPK1), a key player in one type of regulated necrosis (necroptosis), also participates in another type of poly (ADP-ribose) polymerase 1 (PARP1)-dependent regulated necrosis (parthanatos). Various biological signatures of parthanatos were significantly attenuated in Ripk1 mouse embryonic fibroblasts, including PARylation, nuclear translocation of apoptosis-inducing factor, and PARP1-dependent cell death under HO exposure. Hence, we investigated whether RIPK1 regulates the activity of PARP1. RIPK1 activated PARP1 via an interaction with the catalytic domain of PARP1 in the nucleus. Of note, both wild type and kinase-dead mutant RIPK1 induced PARP1 activation and led to PARP1-mediated cell death upon HO insult, demonstrating the kinase-independent regulation of RIPK1 in PARP1 activation. Collectively, our results demonstrate the existence of a kinase-independent role of nuclear RIPK1 in the regulation of PARP1.
在氧化应激的各种病理生理条件下都会发生调节性细胞坏死。在这里，我们报告受体相互作用蛋白激酶 1（RIPK1），一种调节性坏死（细胞焦亡）的关键蛋白，也参与另一种多聚（ADP-核糖）聚合酶 1（PARP1）依赖性调节性坏死（细胞 PAR 化坏死）。在 HO 暴露下，Ripk1 基因敲除的鼠胚胎成纤维细胞中，PAR 化、凋亡诱导因子的核易位和 PARP1 依赖性细胞死亡等多种细胞 PAR 化坏死的特征明显减弱。因此，我们研究了 RIPK1 是否调节 PARP1 的活性。RIPK1 通过与核内 PARP1 的催化结构域相互作用而激活 PARP1。值得注意的是，野生型和激酶失活突变型 RIPK1 均可在 HO 损伤后诱导 PARP1 激活，并导致 PARP1 介导的细胞死亡，表明 RIPK1 在 PARP1 激活中具有激酶非依赖性调控作用。总之，我们的结果表明核 RIPK1 在 PARP1 调节中存在激酶非依赖性作用。
