Abstract
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.
Highlights
Increase the risk for cardiovascular disease [3, 4]
Our results suggest that SUMO1-mediated SUMOylation and SENP1-mediated deSUMOylation are two opposing processes regulating Inducible degrader of the low-density lipoprotein receptor (IDOL) protein levels
IDOL mediates ubiquitination and degradation of low-density lipoprotein receptor (LDLR), and its mutations are tightly associated with abnormal plasma lowdensity lipoprotein (LDL)-C levels in human populations [13, 30, 31]
Summary
SUMOylation can occur on a lysine residue within the inverted SUMOylation consensus motif E/DxKψ (where x stands for any amino acid and ψ for a hydrophobic amino acid) [26]. Quantitative analysis showed that the K293R mutation caused significant decreases in IDOL SUMOylation (Fig. 1E) These results suggest that IDOL is SUMOylated by SUMO1 mainly at the K293 residue. Because there have been no commercial antibodies that can effectively detect endogenous IDOL [10, 12], we examined the level of transfected protein in the absence or presence of UBC9 and SUMO1 in Huh cells. We treated Huh cells transfected with IDOL and UBC9 plus SUMO1 with the proteasome inhibitor MG132 to exclude the possibility that enhanced IDOL protein expression may result from reduced ubiquitination. In control cells following a 1-h pulse (Fig. 5, G–H) These results demonstrate that SENP1 increases LDLR protein and LDL uptake through deSUMOylating IDOL
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