Endosomal lipid accumulation in NPC1 leads to inhibition of PKC, hypophosphorylation of vimentin and Rab9 entrapment

Marc Walter, Fannie W. Chen, Farshad Tamari, Rong Wang, Yiannis A. Ioannou

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

Background information. Within the group of lysosomal storage diseases, NPC1 [NPC (Niemann-Pick type C) 1] disease is a lipidosis characterized by excessive accumulation of free cholesterol as well as gangliosides, glycosphingolipids and fatty acids in the late E/L (endosomal/lysosomal) system (Chen et al., 2005) due to defect in late endosome lipid egress. We have previously demonstrated that expression of the small GTPase Rab9 in NPC1 cells can rescues the lipid transport block phenotype (Walter et al., 2003), albeit by an undefined mechanism. Results. To investigate further the mechanism by which Rab9 facilitates lipid movement from late endosomes we sought to identify novel Rab9 binding/interacting proteins. In the present study, we report that Rab9 interacts with the intermediate filament phosphoprotein vimentin and this interaction is altered by lipid accumulation in late endosomes, which results in inhibition of PKC (protein kinase C) and hypophophoralation of vimentin, leading to late endosome dysfunction. Intermediate filament hypophosphorylation, aggregation and entrapment of Rab9 ultimately leads to transport defects and inhibition of lipid egress from late endosomes. Conclusions. These resutls reveal a previously unappreciated interaction between Rab proteins and intermediate filaments in regulating intracellular lipid transport.

Original languageEnglish
Pages (from-to)141-153
Number of pages13
JournalBiology of the Cell
Volume101
Issue number3
DOIs
StatePublished - 2009

Keywords

  • Intermediate filament
  • Lysosomal storage disease
  • Niemann pick type C1
  • Rab9
  • Vimentin

Fingerprint

Dive into the research topics of 'Endosomal lipid accumulation in NPC1 leads to inhibition of PKC, hypophosphorylation of vimentin and Rab9 entrapment'. Together they form a unique fingerprint.

Cite this