Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, China.
Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, China.
J Biol Chem. 2021 Jan-Jun;296:100032. doi: 10.1074/jbc.RA120.015420. Epub 2020 Nov 23.
Inducible degrader of the low-density lipoprotein receptor (IDOL) is an E3 ubiquitin ligase mediating degradation of low-density lipoprotein (LDL) receptor (LDLR). IDOL also controls its own stability through autoubiquitination, primarily at lysine 293. Whether IDOL may undergo other forms of posttranslational modification is unknown. In this study, we show that IDOL can be modified by small ubiquitin-like modifier 1 at the K293 residue at least. The SUMOylation of IDOL counteracts its ubiquitination and augments IDOL protein levels. SUMOylation and the associated increase of IDOL protein are effectively reversed by SUMO-specific peptidase 1 (SENP1) in an activity-dependent manner. We further demonstrate that SENP1 affects LDLR protein levels by modulating IDOL. Overexpression of SENP1 increases LDLR protein levels and enhances LDL uptake in cultured cells. On the contrary, loss of SENP1 lowers LDLR levels in an IDOL-dependent manner and reduces LDL endocytosis. Collectively, our results reveal SUMOylation as a new regulatory posttranslational modification of IDOL and suggest that SENP1 positively regulates the LDLR pathway via deSUMOylation of IDOL and may therefore be exploited for the treatment of cardiovascular disease.
诱导型低密度脂蛋白受体（IDOL）降解酶是一种 E3 泛素连接酶，介导低密度脂蛋白受体（LDLR）的降解。IDOL 还通过自身泛素化来控制自身的稳定性，主要在赖氨酸 293 上。IDOL 是否可能发生其他形式的翻译后修饰尚不清楚。在本研究中，我们表明 IDOL 至少可以在 K293 残基上被小泛素样修饰物 1 修饰。IDOL 的 SUMO 化可拮抗其泛素化并增加 IDOL 蛋白水平。SUMO 特异性肽酶 1（SENP1）以活性依赖的方式有效地逆转 SUMO 化及其伴随的 IDOL 蛋白增加。我们进一步证明，SENP1 通过调节 IDOL 影响 LDLR 蛋白水平。SENP1 的过表达增加了培养细胞中的 LDLR 蛋白水平并增强了 LDL 摄取。相反，SENP1 的缺失以 IDOL 依赖的方式降低 LDLR 水平并减少 LDL 内吞。总之，我们的结果揭示了 SUMO 化是 IDOL 的一种新的翻译后修饰调节方式，并表明 SENP1 通过 IDOL 的去 SUMO 化正向调节 LDLR 途径，因此可能被用于心血管疾病的治疗。
