NAD(P)H quinone oxidoreductase 1 inhibits the proteasomal degradation of homocysteine-inducible endoplasmic reticulum protein.
NAD(P)H quinone oxidoreductase 1 inhibits the proteasomal degradation of homocysteine-inducible endoplasmic reticulum protein.
复制标题
NAD(P)H 醌氧化还原酶 1 抑制同型半胱氨酸诱导的内质网蛋白的蛋白酶体降解。
DOI：
10.1016/j.bbrc.2016.04.057
复制
发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Komano H.
中科院分区：
文献类型：
--
作者：
Maeda T;Tanabe-Fujimura C;Fujita Y Abe C;Nanakida Y;Zou K;Liu J;Liu S;Nakajima T;Komano H.
同型半胱氨酸诱导的内质网 (ER) 蛋白 (Herp) 是 ER 应激诱导的 ER 相关降解 (ERAD) 的关键调节成分，与糖尿病小鼠模型中的胰岛素分泌过多有关。 Herp 表达受到严格调控。此外，Herp 是一种高度不稳定的蛋白质，可与多种蛋白质相互作用，这是泛素化蛋白质的特征。之前，我们报道过 Herp 降解不需要泛素化。此外，我们发现 Herp 的赖氨酸残基（被 E3 泛素连接酶泛素化）不足以调节 Herp 降解。在这项研究中，我们发现 NAD(P)H 醌氧化还原酶 1 (NQO1) 介导的 Herp 靶向蛋白酶体参与了 Herp 降解。此外，我们发现滑膜蛋白缺失细胞中的 Herp 蛋白水平显着升高。 E3 泛素连接酶滑膜蛋白是 ERAD 的核心成分，参与核因子 E2 相关因子 2 (Nrf2) 的降解，调节细胞活性氧。此外，NQO1 是 Nrf2 的靶标。因此，我们的研究结果表明，NQO1 可以通过间接调节滑膜增生蛋白来稳定 Herp 蛋白的表达。
Homocysteine-induced endoplasmic reticulum (ER) protein (Herp) is an ER stress-inducible key regulatory component of ER-associated degradation (ERAD) that has been implicated in insulin hypersecretion in diabetic mouse models. Herp expression is tightly regulated. Additionally, Herp is a highly labile protein and interacts with various proteins, which are characteristic features of ubiquitinated protein. Previously, we reported that ubiquitination is not required for Herp degradation. In addition, we found that the lysine residues of Herp (which are ubiquitinated by E3 ubiquitin ligase) are not sufficient for regulation of Herp degradation. In this study, we found that NAD(P)H quinone oxidoreductase 1 (NQO1)-mediated targeting of Herp to the proteasome was involved in Herp degradation. In addition, we found that Herp protein levels were markedly elevated in synoviolin-null cells. The E3 ubiquitin ligase synoviolin is a central component of ERAD and is involved in the degradation of nuclear factor E2-related factor-2 (Nrf2), which regulates cellular reactive oxygen species. Additionally, NQO1 is a target of Nrf2. Thus, our findings indicated that NQO1 could stabilize Herp protein expression via indirect regulation of synoviolin.