期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 296, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1074/jbc.RA120.015420
关键词
-
资金
- NNSF of China [31690102, 31600651, 91954203]
- Ministry of Science and Technology of China [2018YFA0800700]
- 111 Project of Ministry of Education of China [B16036]
This study shows that IDOL can be modified by SUMOylation, which counteracts its ubiquitination and increases IDOL protein levels. Additionally, SENP1 modulates the LDLR pathway by deSUMOylating IDOL, thus influencing LDLR protein levels and LDL endocytosis. These findings suggest potential therapeutic implications for cardiovascular disease.
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 post-translational 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.
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