SUMOylation of the ubiquitin ligase IDOL decreases LDL receptor levels and is reversed by SENP1

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 post-translational modification is unknown. In this study, we show that IDOL can be modified by small ubiquitin-like modifier 1 (SUMO1) 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 post-translational 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.

Ablation of Plasma Prekallikrein Decreases Low-Density Lipoprotein Cholesterol by Stabilizing Low-Density Lipoprotein Receptor and Protects Against Atherosclerosis

“…We further knocked down KLKB1 using siRNA (Figure S1F) and detected increased levels of LDLR protein (Figure 1E). Inducible degrader of the LDLR as the E3 ubiquitin ligase known to mediate LDLR degradation [26][27][28] was the positive control. In line with LDLR elevation, the uptake of DiI-labeled LDL was dramatically increased in KLKB1 knockdown cells (Figure 1F and 1G).…”

Isocoumarins and Benzoquinones with Their Proprotein Convertase Subtilisin/Kexin Type 9 Expression Inhibitory Activities from Dried Roots of Lysimachia vulgaris

“…Upregulation of SREBP2 has been known to activate PCSK9 expression in the HepG2 hepatocytes. − Hence, it can be inferred that inhibition of SREBP2 enables the downregulation of PCSK9 expression, increasing LDL uptake. − Moreover, the current study demonstrated that 8′ Z ,11′ Z -octadecadienyl-6,8-dihydroxyisocoumarin ( 1 ) and 5- O -methylembelin ( 3 ) slightly downregulate IDOL mRNA expression. In contrast, LXRs induce the transcriptional expression of IDOL, which is involved in degrading LDLR and thereby inhibiting LDL uptake. − …”

“…The known structure compounds (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) were identified by comparison of their spectroscopic data with the reported values, as 5-O-methylembelin (3), 20 5-O-methylrapanone (4), 21 9-hydroxy-(9S,10E,12Z,15Z)-octadecatrienoic acid (5), 22 9-oxo-(10E,12E)-octadecadienoic acid (6), 23 9-oxo-(10E,12Z)-octadecadienoic acid (7), 23 2,3-dihydroxypropyl-(10Z,13Z)-nonadecadienoate (8), 24 2,3-dihydroxypropylpentadecadienoate ( 9), 25 1-monopalmitoyl-rac-glycerol (10), 26 monononadecanoin (11), 27 methyl linoleate ( 12), 6 linoleic acid (13), 6 oleic acid ( 14), 24 capric acid (15), 28 lauric acid (16), 29 palmitic acid (17), 30 stearic acid (18), 31 (+)-demethoxylpinoresinol (19), 6 (+)-pinoresinol (20), 6 trans-cinnamic acid (21), 32 and cis-ferulic acid (22). 33 The known compounds (3)…”

“…Despite the efficacy of statins in lowering low-density lipoprotein cholesterol (LDLC) levels and decreasing cardiovascular disease risk, − there are also challenges related to both their insufficient therapeutic effects and side effects in patients with familial hypercholesterolemia. , The LDL receptor (LDLR) plays a prominent role in lowering the LDLC level of the blood by trafficking LDLC from the blood into cells. − Two major regulator proteins of LDLRs, proprotein convertase subtilisin/kexin type 9 (PCSK9) and inducible degrader of the low-density lipoprotein receptor (IDOL), are known to regulate LDLR degradation. − PCSK9 binds to the extracellular domain of LDLRs on the cell membrane, promoting the degradation and preventing the recycling of LDLR. This leads to a low level of LDLR in the cell membrane and less uptake of LDLC into the cell.…”

SUMOylation of microtubule-cleaving enzyme KATNA1 promotes microtubule severing and neurite outgrowth

“…The tertiary structures and modification processes of SUMOylation are highly similar to those of ubiquitination (39). For example, the K293 residue in low-density lipoprotein receptor (IDOL) is modified by both SUMOylation and ubiquitination, wherein SUMOylation can counteract ubiquitination to increase the levels of IDOL (40). The deubiquitinating enzyme ubiquitin carboxy-terminal hydrolase 37 (USP37) is modified by SUMOylation and ubiquitination at different sites, and SUMOylation at K452 promotes subsequent ubiquitination of K148 and K389 (41).…”