The NRF2-p62 Axis in the Cross-Talk between Proteasomal and Lysosomal Degradation

心力衰竭是人类无法治愈的死亡率和发病率的主要原因。蛋白质的降解 泛素-蛋白酶体系统(UPS)和自噬-溶酶体途径(ALP)是心肌蛋白的关键途径 质量控制，将错误折叠的蛋白质在心肌细胞中的水平和毒性降至最低。蛋白 UPS和ALP功能障碍导致的质量控制不足与心脏的发育有关 由多种心脏疾病引起的衰竭，包括压力超负荷(PO)障碍。蛋白酶体抑制 激活ALP，而ALP损伤可能会影响UPS性能，这表明存在复杂的相互作用 UPS和ALP功能障碍之间的关系。然而，这种在患病心脏中的相互作用及其潜在的 机制还有待定义。因此，这项研究项目的长期目标是勾勒出 UPS-ALP串扰的分子基础。文献和我们的初步研究表明，NRF2(核因子- 红系相关因子2)及其靶基因p62/SQSTM1可能作为一种分子链作用于 UPS的表现是由于ALP不足，但这一点仍有待于心脏方面的研究。因此，我们建议 确定Nrf2-p62轴在调节压力超负荷心脏的ALP-UPS串扰中的作用。这个 有待检验的中心假说是，Nrf2-p62轴的激活在 压力超负荷心脏ALP不足对UPS功能的损害。我们将推行2项 明确的目标。目标1将确定Nrf2在诱导心脏UPS损伤和适应不良中的作用 碱性磷酸酶损伤致PO心脏重塑。目标2将研究Nrf2的分子机制 加剧碱性磷酸酶不足心脏的心脏损伤，验证了Nrf2诱导p62的假设 损害碱性磷酸酶缺乏的心脏的UPS表现。这个项目可能会提供新的机械洞察力 UPS-ALP在心脏中相互作用，并建立了一种新的概念，即在激活Nrf2的同时增强ALP是一种 比单独激活Nrf2更好的治疗心脏病的策略。

Heart failure is a leading cause of human mortality and morbidity without a cure. Protein degradation by the ubiquitin-proteasome system (UPS) and the autophagic-lysosomal pathway (ALP) is pivotal to cardiac protein quality control which acts to minimize the level and toxicity of misfolded proteins in cardiomyocytes. Protein quality control inadequacy resulting from UPS and ALP dysfunctions is implicated in the development of heart failure from a variety of heart diseases including pressure overload (PO) disorders. Proteasome inhibition activates ALP while ALP impairment can compromise UPS performance, suggesting an intricate interplay between UPS and ALP dysfunctions. However, such interplay in diseased hearts and its underlying mechanisms remain to be defined. Therefore the long term goal of this research project is to delineate the molecular basis of UPS-ALP crosstalk. Literature and our pilot studies suggest that NRF2 (nuclear factor- erythroid 2-related factor 2) and its target gene p62/SQSTM1 may act as a molecular link in the impairment of UPS performance by ALP insufficiency but this remains to be established in the heart. Hence, we propose to determine the role of the Nrf2-p62 axis in regulating ALP-UPS cross-talk in pressure overloaded hearts. The central hypothesis to be tested is that activation of the Nrf2-p62 axis plays a major mediating role in the impairment of UPS performance by ALP insufficiency in pressure overloaded hearts. We will pursue 2 specific aims. Aim 1 will determine the role of Nrf2 in the induction of cardiac UPS impairment and maladaptive remodeling by ALP impairment in PO hearts. Aim 2 will investigate the molecular mechanism by which Nrf2 exacerbates cardiac injury in ALP insufficient hearts, testing the hypothesis that induction of p62 by Nrf2 impairs UPS performance in ALP deficient hearts. This project will likely provide new mechanistic insight into UPS-ALP interplay in the heart and establish a new concept that enhancing ALP while activating Nrf2 is a better strategy than Nrf2 activation alone for treating heart disease.