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Editorial
. 2016 Feb 5;118(3):371-3.
doi: 10.1161/CIRCRESAHA.116.308191.

Foiling IDOL to Help Control Cholesterol

Andrew J Brown  1 , Joanne Hsieh  2
Affiliations
Editorial

Foiling IDOL to Help Control Cholesterol

Andrew J Brown et al. Circ Res. .
No abstract available

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Figures

Figure 1
Figure 1. The role of ubiquitylation in the regulation of LDLR
Boxed items are treatments currently approved to lower LDL cholesterol. (1) Statin treatment targets HMGCR, the rate-limiting enzyme of the mevalonate pathway, lowering cellular cholesterol and activating SREBP-2. (2) SREBP-2 is also inhibited by an E3 ubiquitin ligase MARCH6, and transcriptionally induces LDLR expression, which increases LDL uptake. (3) LDLR is bound by extracellular PCSK9, leading to its lysosomal degradation. Anti-PCSK9 monoclonal antibodies including evolocumab and alirocumab are approved to block the PCSK9-induced LDLR degradation to maintain LDL uptake. (4) The sterol sensor LXR transcriptionally induces IDOL which, (5) with its cognate E2 ubiquitin ligase UBE2D, ubiquitylates LDLR for lysosomal degradation. (6) LDLR’s subsequent deubiquitylation by USP8 is necessary to sort it into the lysosomal degradation pathway. (7) Inhibition of DUB activity has been shown to induce IDOL expression via an unknown transcription factor binding site (TFBS). (8) MARCH6 also inhibits HMGCR, lowering cholesterol biosynthetic intermediates that would activate LXR and IDOL transcription. The coloured proteins depict the new pathway described in this issue by Nelson and Sorrentino et al. (9) USP2’s DUB activity decreases the ubiquitylation of both IDOL and LDLR, protecting the former from proteasomal degradation and the latter from lysosomal degradation. USP2 activity therefore maintains membrane expression of LDLR and LDL uptake.
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Comment on

References

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