Metabolism
The E3 Ubiquitin Ligase IDOL Induces the Degradation of the Low Density Lipoprotein Receptor Family Members VLDLR and ApoER2*

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We have previously identified the E3 ubiquitin ligase-inducible degrader of the low density lipoprotein receptor (LDLR) (Idol) as a post-translational modulator of LDLR levels. Idol is a direct target for regulation by liver X receptors (LXRs), and its expression is responsive to cellular sterol status independent of the sterol-response element-binding proteins. Here we demonstrate that Idol also targets two closely related LDLR family members, VLDLR and ApoE receptor 2 (ApoER2), proteins implicated in both neuronal development and lipid metabolism. Idol triggers ubiquitination of the VLDLR and ApoER2 on their cytoplasmic tails, leading to their degradation. We further show that the level of endogenous VLDLR is sensitive to cellular sterol content, Idol expression, and activation of the LXR pathway. Pharmacological activation of the LXR pathway in mice leads to increased Idol expression and to decreased Vldlr levels in vivo. Finally, we establish an unexpected functional link between LXR and Reelin signaling. We demonstrate that LXR activation results in decreased Reelin binding to VLDLR and reduced Dab1 phosphorylation. The identification of VLDLR and ApoER2 as Idol targets suggests potential roles for this LXR-inducible E3 ligase in the central nervous system in addition to lipid metabolism.

Cholesterol Metabolism
Lipoprotein Receptor
Metabolism
Nuclear Receptors
Ubiquitin Ligase
LXR

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*

This work was supported, in whole or in part, by National Institutes of Health Grants HL066088 and HL090553 (to P. T.).

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S6.

1

These authors contributed equally to this work.

2

Supported by the Canadian Institutes of Health Research. Alberta Heritage Foundation for Medical Research Scholar. Canada Research Chair in Innate Immunity.

3

Supported by grants from the Academy of Finland and the Sigrid Juselius Foundation.

4

Supported by the Fonds zur Förderung der Wissenschaftlichen Forschung and the Herzfelder'sche Familienstiftung.

5

Investigator of the Howard Hughes Medical Institute.