Abstract
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. 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 plasma membrane LDLR levels and LDL uptake. In murine oligodendrocytes, Ndrg1 silencing not only results in reduced LDL uptake but also in downregulation of the oligodendrocyte differentiation factor Olig2. Both phenotypes are rescued by co-silencing of Idol, suggesting that ligand uptake through 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 might impair lipid processing and differentiation of myelinating cells.
Keywords:
Cholesterol; Endocytosis; IDOL; Multivesicular body; NDRG1.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Androstenes / pharmacology
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Animals
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Basic Helix-Loop-Helix Transcription Factors / biosynthesis
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Differentiation
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Cell Line, Tumor
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Cell Membrane / metabolism
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Charcot-Marie-Tooth Disease / genetics
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Charcot-Marie-Tooth Disease / metabolism*
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Down-Regulation
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Endocytosis / genetics
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Endosomal Sorting Complexes Required for Transport / biosynthesis
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Endosomes / metabolism*
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GTP-Binding Proteins / genetics
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GTP-Binding Proteins / metabolism
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HEK293 Cells
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Lipoproteins, LDL / metabolism
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Mice
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Nerve Tissue Proteins / biosynthesis
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Nerve Tissue Proteins / metabolism
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Oligodendrocyte Transcription Factor 2
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Protein Transport / genetics
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RNA Interference
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RNA, Small Interfering
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Receptors, LDL / metabolism*
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Refsum Disease / genetics
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Refsum Disease / metabolism*
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Ubiquitin-Protein Ligases / metabolism
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Ubiquitination
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Vesicular Transport Proteins / genetics
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Vesicular Transport Proteins / metabolism
Substances
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Androstenes
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Basic Helix-Loop-Helix Transcription Factors
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Cell Cycle Proteins
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Endosomal Sorting Complexes Required for Transport
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Intracellular Signaling Peptides and Proteins
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Lipoproteins, LDL
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N-myc downstream-regulated gene 1 protein
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Nerve Tissue Proteins
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Olig2 protein, mouse
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Oligodendrocyte Transcription Factor 2
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RNA, Small Interfering
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Receptors, LDL
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Vesicular Transport Proteins
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early endosome antigen 1
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3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one
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MYLIP protein, human
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Ubiquitin-Protein Ligases
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GTP-Binding Proteins
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RABAC1 protein, human
Supplementary concepts
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Neuropathy, hereditary motor and sensory, LOM type