RGD Reference Report - The small GTPase Cdc42 interacts with Niemann-Pick C1-like 1 (NPC1L1) and controls its movement from endocytic recycling compartment to plasma membrane in a cholesterol-dependent manner. - Rat Genome Database

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The small GTPase Cdc42 interacts with Niemann-Pick C1-like 1 (NPC1L1) and controls its movement from endocytic recycling compartment to plasma membrane in a cholesterol-dependent manner.

Authors: Xie, C  Li, N  Chen, ZJ  Li, BL  Song, BL 
Citation: Xie C, etal., J Biol Chem. 2011 Oct 14;286(41):35933-42. Epub 2011 Aug 15.
RGD ID: 5688279
Pubmed: PMID:21844200   (View Abstract at PubMed)
PMCID: PMC3195612   (View Article at PubMed Central)
DOI: DOI:10.1074/jbc.M111.270199   (Journal Full-text)

Niemann-Pick C1-like 1 (NPC1L1) is a multi-transmembrane protein that mediates the absorption of dietary and biliary cholesterol through vesicular endocytosis. The subcellular localization of NPC1L1 is regulated by cholesterol. Cholesterol depletion induces the transport of NPC1L1 to plasma membrane (PM) from endocytic recycling compartment that requires MyoVb.Rab11a.Rab11-FIP2 triple complex, and cholesterol-replenishment renders the internalization of NPC1L1 together with cholesterol. Here, we find that GTP-bound Cdc42 interacts with NPC1L1. Cholesterol depletion regulates the activation of Cdc42 and enhances NPC1L1-Cdc42 interaction. Overexpression of constitutive GTP-bound Cdc42 mutant form or knockdown of Cdc42 inhibits the transport of NPC1L1 to the PM and disturbs the cholesterol-regulated binding of NPC1L1 to Rab11a, MyoVb, and actin. Knockdown of Cdc42 downstream effectors N-WASP or Arp3 also leads to the similar results. In liver-specific Cdc42 knock-out (Cdc42 LKO) mice, NPC1L1 fails to localize to bile canaliculi, and the biliary cholesterol cannot be efficiently reabsorbed. These results indicate that Cdc42 controls the cholesterol-regulated transport and localization of NPC1L1, and plays a role in cholesterol absorption.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Cdc42Ratpositive regulation of intracellular protein transport  IMP  RGD 
Actr3Ratpositive regulation of protein binding  IMP Npc1l1 more ...RGD 
Actr3Ratpositive regulation of protein localization to plasma membrane  IMP Npc1l1RGD 

Objects Annotated

Genes (Rattus norvegicus)
Actr3  (actin related protein 3)
Cdc42  (cell division cycle 42)


Additional Information