McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, 6159 Wisconsin Institute for Medical Research, 1111 Highland Avenue, Madison, WI 53705, USA.
Mol Cell. 2011 Jul 22;43(2):180-91. doi: 10.1016/j.molcel.2011.06.017.
Activation of NF-κB, pivotal for immunity and oncogenesis, is tightly controlled by multiple feedback mechanisms. In response to DNA damage, SUMOylation of NEMO (NF-κB essential modulator) is critical for NF-κB activation; however, the SUMO proteases and feedback mechanisms involved remain unknown. Here we show that among the six known Sentrin/SUMO-specific proteases (SENPs), only SENP2 can efficiently associate with NEMO, deSUMOylate NEMO, and inhibit NF-κB activation induced by DNA damage. We further show that NF-κB induces SENP2 (and SENP1) transcription selectively in response to genotoxic stimuli, which involves ataxia telangiectasia mutated (ATM)-dependent histone methylation of SENP2 promoter κB regions and NF-κB recruitment. SENP2 null cells display biphasic NEMO SUMOylation and activation of IKK and NF-κB, and higher resistance to DNA damage-induced cell death. Our study establishes a self-attenuating feedback mechanism selective to DNA damage-induced signaling to limit NF-κB-dependent cell survival responses.
NF-κB 的激活对于免疫和肿瘤发生至关重要，其受到多种反馈机制的严格控制。在 DNA 损伤的反应中，NEMO（NF-κB 必需调节剂）的 SUMO 化对于 NF-κB 的激活至关重要；然而，涉及的 SUMO 蛋白酶和反馈机制仍不清楚。在这里，我们发现，在六种已知的 Sentrin/SUMO 特异性蛋白酶（SENPs）中，只有 SENP2 可以有效地与 NEMO 结合，去 SUMO 化 NEMO，并抑制 DNA 损伤诱导的 NF-κB 激活。我们进一步表明，NF-κB 选择性地诱导 SENP2（和 SENP1）转录，以响应遗传毒性刺激，这涉及共济失调毛细血管扩张突变（ATM）依赖性 SENP2 启动子 κB 区域的组蛋白甲基化和 NF-κB 的募集。SENP2 缺失细胞显示出 NEMO SUMO 化的双相性和 IKK 和 NF-κB 的激活，以及对 DNA 损伤诱导的细胞死亡的更高抗性。我们的研究建立了一种自我衰减的反馈机制，选择性地针对 DNA 损伤诱导的信号，以限制 NF-κB 依赖性细胞存活反应。
