Nrf2 signaling is vital for protecting cells against oxidative stress. However, its hyperactivation is frequently found in liver cancer through excessive build‐up of p62/SQSTM1 bodies that sequester Keap1, an adaptor of the E3‐ubiquitin ligase complex for Nrf2. Here, we report that the Bax‐binding protein MOAP‐1 regulates p62‐Keap1‐Nrf2 signaling through disruption of p62 bodies. Upon induction of cellular stresses that stimulate formation of p62 bodies, MOAP‐1 is recruited to p62 bodies and reduces their levels independent of the autophagy pathway. MOAP‐1 interacts with the PB1‐ZZ domains of p62 and interferes with its self‐oligomerization and liquid–liquid phase separation, thereby disassembling the p62 bodies. Loss of MOAP‐1 can lead to marked upregulation of p62 bodies, enhanced sequestration of Keap1 by p62 and hyperactivation of Nrf2 antioxidant target genes. MOAP‐1‐deficient mice exhibit an elevated tumor burden with excessive levels of p62 bodies and Nrf2 signaling in a diethylnitrosamine (DEN)‐induced hepatocarcinogenesis model. Together, our data define MOAP‐1 as a negative regulator of Nrf2 signaling via dissociation of p62 bodies.

中文翻译：

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MOAP-1 介导的 p62/SQSTM1 体解离释放 Keap1 并抑制 Nrf2 信号传导

Nrf2 信号传导对于保护细胞免受氧化应激至关重要。然而，它的过度激活经常在肝癌中通过过度积累的 p62/SQSTM1 小体来隔离 Keap1，Keap1 是 Nrf2 的 E3 泛素连接酶复合物的适配器。在这里，我们报告了 Bax 结合蛋白 MOAP-1 通过破坏 p62 小体来调节 p62-Keap1-Nrf2 信号传导。在诱导刺激 p62 小体形成的细胞应激后，MOAP-1 被招募到 p62 小体并降低其水平，而与自噬途径无关。MOAP-1 与 p62 的 PB1-ZZ 结构域相互作用并干扰其自寡聚和液液相分离，从而分解 p62 体。MOAP-1 的缺失可导致 p62 小体的显着上调，通过 p62 增强 Keap1 的隔离和 Nrf2 抗氧化靶基因的过度激活。在二乙基亚硝胺 (DEN) 诱导的肝癌发生模型中，MOAP-1 缺陷小鼠表现出肿瘤负荷升高，p62 小体和 Nrf2 信号水平过高。总之，我们的数据将 MOAP-1 定义为通过 p62 体解离的 Nrf2 信号传导的负调节剂。