NDRG1 functions in LDL receptor trafficking by regulating endosomal recycling and degradation

Vilja Pietiäinen1,2, Boris Vassilev2,3, Tomas Blom2,3, Wei Wang2,3, Jessica K. Nelson4, Robert Bittman5, Nils Bäck2, Noam Zelcer4, Elina Ikonen2,3
1Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
2Institute of Biomedicine/Anatomy, University of Helsinki, Helsinki, Finland
3Minerva Foundation Institute for Medical Research, Helsinki, Finland
4Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
5Department of Chemistry and Biochemistry, Queens College of The City University of New York, Flushing, NY, USA

Tóm tắt

N-myc downstream-regulated gene 1 (NDRG1) mutations cause Charcot-Marie-Tooth Disease type 4D (CMT4D). However, the cellular function of NDRG1 and how it causes CMT4D are poorly understood. We report that NDRG1 silencing in epithelial cells results in decreased uptake of low-density lipoprotein (LDL) due to reduced LDL receptor (LDLR) abundance at the plasma membrane (PM). This is accompanied by the accumulation of LDLR in enlarged EEA1-positive endosomes that contain numerous intraluminal vesicles and sequester ceramide. Concomitantly, LDLR ubiquitylation is increased but its degradation is reduced and ESCRT (Endosomal sorting complex required for transport) proteins are downregulated. Co-depletion of IDOL (Inducible degrader of the LDLR), which ubiquitylates the LDLR and promotes its degradation, rescues PM LDLR levels and LDL uptake. In oligodendrocytes, Ndrg1 silencing not only results in reduced LDL uptake but also downregulation of the oligodendrocyte differentiation factor Olig2. Both phenotypes are rescued by co-silencing of Idol, suggesting that ligand uptake via LDLR family members controls oligodendrocyte differentiation. These findings identify NDRG1 as a novel regulator of multivesicular body formation and endosomal LDLR trafficking. The deficiency of functional NDRG1 in CMT4D may impair lipid processing and differentiation of myelinating cells.

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