The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2.
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.
Hong
Cynthia
C
Department of Pathology and Laboratory Medicine and the Howard Hughes Medical Institute, University of California, Los Angeles, California 90095, USA.
Duit
Sarah
S
Jalonen
Pilvi
P
Out
Ruud
R
Scheer
Lilith
L
Sorrentino
Vincenzo
V
Boyadjian
Rima
R
Rodenburg
Kees W
KW
Foley
Edan
E
Korhonen
Laura
L
Lindholm
Dan
D
Nimpf
Johannes
J
van Berkel
Theo J C
TJ
Tontonoz
Peter
P
Zelcer
Noam
N
D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D015151:Immunoblotting; D026502:LDL-Receptor Related Proteins; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D018110:Receptors, Lipoprotein / Q000235:genetics / Q000378:metabolism*; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D001565:Benzoates; D001596:Benzylamines; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D006845:Hydrocarbons, Fluorinated; D026502:LDL-Receptor Related Proteins; D000071518:Liver X Receptors; D009419:Nerve Tissue Proteins; D057093:Orphan Nuclear Receptors; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; D000091042:Reelin Protein; D012697:Serine Endopeptidases; D013449:Sulfonamides; D044767:Ubiquitin-Protein Ligases; C103773:Dab1 protein, mouse; C473027:GW 3965; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C036053:VLDL receptor; C098773:low density lipoprotein receptor-related protein 8; C542022:Mylip protein, mouse; C000717127:RELN protein, human; C000717128:Reln protein, mouse