Background
The enzymes of the ubiquitylation pathway play a pivotal role in a number of cellular processes including the regulated and targeted proteasome-dependent degradation of substrate proteins. Three classes of enzymes are involved in the process of ubiquitylation; activating enzymes (E1s), conjugating enzymes (E2s) and protein ligases (E3s). Inducible Degrader of LDLR (IDOL) is a member of the E3 protein ligase family and cloning of the human gene was first described by Olsson et al. (1999). IDOL is a RING finger domain ubiquitin E3 ligase that is up-regulated by the sterol-activated transcription factors LXR alpha and LXR beta. IDOL activity leads to ubiquitylation and degradation of the low density lipoprotein (LDL) receptor (LDLR). LDLR is essential for the uptake of LDL cholesterol and the regulation of plasma lipoprotein levels and lipid homeostasis (Zelcer et al., 2009; Zhang et al., 2011). An inherited loss-of-function mutation in the LDLR gene in humans or poor diet can elevate plasma LDL levels, reduce LDL clearance and accelerate atherosclerosis and the risk of cardiovascular disease (Tolleshaug et al., 1983; Brown and Goldstein 1986).
References
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Olsson PA, Korhonen L, Mercer E A, Lindholm D. (1999) MIR is a novel ERM-like protein that interacts with myosin regulatory light chain and inhibits neurite outgrowth. J Biol Chem 274, 36288-36292.
Tolleshaug H, Hobgood KK, Brown MS, Goldstein JL. (1983) The LDL receptor locus in familial hypercholesterolemia: multiple mutations disrupt transport and processing of a membrane receptor. Cell 32, 941-51.
Zelcer N, Hong C, Boyadjian R, Tontonoz P. (2009) LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor. Science 325, 100-4.
Zhang L, Fairall L, Goult BT, Calkin AC, Hong C, Millard CJ, Tontonoz P, Schwabe JW. (2011) The IDOL-UBE2D complex mediates sterol-dependent degradation of the LDL receptor. Genes Dev 25, 1262-74.