PPARγ 与 UBR5/ATMIN 相互作用促进 DNA 修复以维持血管内皮稳态。
PPARγ Interaction with UBR5/ATMIN Promotes DNA Repair to Maintain Endothelial Homeostasis.
机构信息
The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA.
California Institute for Quantitative Biosciences, Department of Cellular and Molecular Pharmacology, University of California-San Francisco, San Francisco, CA 94158, USA; Department of Pharmaceutical Chemistry, University of California-San Francisco, San Francisco, CA 94158, USA.
出版信息
Cell Rep. 2019 Jan 29;26(5):1333-1343.e7. doi: 10.1016/j.celrep.2019.01.013.
Using proteomic approaches, we uncovered a DNA damage response (DDR) function for peroxisome proliferator activated receptor γ (PPARγ) through its interaction with the DNA damage sensor MRE11-RAD50-NBS1 (MRN) and the E3 ubiquitin ligase UBR5. We show that PPARγ promotes ATM signaling and is essential for UBR5 activity targeting ATM interactor (ATMIN). PPARγ depletion increases ATMIN protein independent of transcription and suppresses DDR-induced ATM signaling. Blocking ATMIN in this context restores ATM activation and DNA repair. We illustrate the physiological relevance of PPARγ DDR functions by using pulmonary arterial hypertension (PAH) as a model that has impaired PPARγ signaling related to endothelial cell (EC) dysfunction and unresolved DNA damage. In pulmonary arterial ECs (PAECs) from PAH patients, we observed disrupted PPARγ-UBR5 interaction, heightened ATMIN expression, and DNA lesions. Blocking ATMIN in PAH PAEC restores ATM activation. Thus, impaired PPARγ DDR functions may explain the genomic instability and loss of endothelial homeostasis in PAH.
利用蛋白质组学方法，我们发现过氧化物酶体增殖物激活受体 γ（PPARγ）通过与 DNA 损伤传感器 MRE11-RAD50-NBS1（MRN）和 E3 泛素连接酶 UBR5 的相互作用，具有 DNA 损伤反应（DDR）功能。我们表明，PPARγ 促进 ATM 信号转导，并且对于靶向 ATM 相互作用蛋白（ATMIN）的 UBR5 活性是必需的。PPARγ 耗竭增加了 ATMIN 蛋白的表达，而不依赖于转录，并抑制 DDR 诱导的 ATM 信号转导。在这种情况下阻断 ATMIN 可恢复 ATM 的激活和 DNA 修复。我们通过使用肺动脉高压（PAH）作为模型来阐明 PPARγ DDR 功能的生理相关性，该模型与内皮细胞（EC）功能障碍和未解决的 DNA 损伤相关的 PPARγ 信号转导受损有关。在 PAH 患者的肺动脉内皮细胞（PAEC）中，我们观察到 PPARγ-UBR5 相互作用中断、ATMIN 表达升高和 DNA 损伤。在 PAH PAEC 中阻断 ATMIN 可恢复 ATM 的激活。因此，受损的 PPARγ DDR 功能可能解释了 PAH 中的基因组不稳定性和内皮细胞稳态的丧失。
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