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

Abstract

Summary 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.

A Unique TGFB1-Driven Genomic Program Links Astrocytosis, Low-Grade Inflammation and Partial Demyelination in Periplaques of Spinal Cords from Progressive Multiple Sclerosis Patients

“…While a previous study showed that NDRG1 is specifically silenced in the NAWM of MS patients [19][20][21], we found that NDRG1 was constantly downregulated in spinal cord periplaques as compared to adjacent NAWM. We thus sought to identify candidate soluble factors (in particular immune molecules) that would be potentially involved in a repression of NDRG1 expression in periplaque areas of MS spinal cords.…”

“…Such a finding has to be interpreted in light of a recent work demonstrating that NDRG1 is also the only oligodendrocyte-specific gene whose silencing was demonstrated in the NAWM of MS patients. These data, while further supporting the role of NDRG1 as a master regulator of oligodendrocyte differentiation and myelin maintenance [19][20][21], suggest also that NDRG1 may be a major target of a yet uncharacterized process leading to diffuse myelin alterations in periplaques. When using NDRG1 as a bait gene to identify a large co-expression module in oligodendrocytes, we found that only 3 genes coding for myelin proteins co-downregulated with NDRG1 in periplaques: MBP, MOBP and PLP1.…”

“…We identified a set of 44 co-downregulated genes ( Figure 4 and Table 1) among which NDRG1 was the only hub gene previously recognized as being specifically expressed by oligodendrocytes in the central nervous system [19][20][21]. A co-expression network was generated with the set of genes that are constantly downregulated in periplaques as compared to adjacent NAWM.…”

The Metastasis Suppressor, N-MYC Downstream-regulated Gene-1 (NDRG1), Down-regulates the ErbB Family of Receptors to Inhibit Downstream Oncogenic Signaling Pathways

“…Interestingly, previous studies have shown that NDRG1 is highly expressed in the endosome and plays an important role in endosomal dynamics (73), with this latter protein being found to promote endosomal degradation of the low density lipoprotein receptor (LDLR) (74). Moreover, NDRG1 depletion was found to result in abnormal endosomal sequestration of LDLR, suggesting that NDRG1 function is required for endosomal maturation (74). Similarly to LDLR, membrane EGFR is also degraded after internalization by receptor-mediated endocytosis (44).…”

Rhinoviruses and Their Receptors: Implications for Allergic Disease

“…ICAM-1 is located at the plasma membrane and also in the cytoplasm on the apicolateral portions of the airway epithelial cells [67, 68], whereas LDLR family members are endocytic recycling receptors found mainly in recycling endosomes and, to a lesser extent, at the plasma membrane [69, 70]. Although the structural changes in the viral capsid of both major and minor group RVs similarly result in a stepwise transition from native virus to subviral particles and release of the RNA, some key virus binding properties are receptor specific [50, 71].…”