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

Cynthia Hong, Sarah Duit, Pilvi Jalonen, Ruud Out, Lilith Scheer, Vincenzo Sorrentino, Rima Boyadjian, Kees C. W. Rodenburg, Edan Foley, Laura Korhonen, Dan Lindholm, Johannes Nimpf, Theo J. C. van Berkel, Peter Tontonoz, Noam Zelcer

Research output: Contribution to journalArticle*Academicpeer-review

Abstract

We have previously identified the E3-ubiquitin ligase Inducible Degrader of the LDLR (Idol)1 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, the very low density lipoprotein receptor (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 tail, 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 signalling. 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 CNS in addition to lipid metabolism
Original languageEnglish
Pages (from-to)19720-19726
JournalJournal of biological chemistry
Volume285
Issue number26
DOIs
Publication statusPublished - 2010

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