Cdc42 Regulates the Transport of NPC1L1 towards Plasma Membrane

Niemann-Pick C1-like 1 (NPC1L1) plays an essential role in dietary and biliary cholesterol absorption in mammals. 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. However, it’s unclear how cholesterol regulates the translocation of NPC1L1.

 

In this study, XIE Chang, under the supervision of Dr. SONG Baoliang, found that GTP-bound Cdc42 interacts with NPC1L1. Cholesterol depletion regulates the activation of Cdc42 and enhances NPC1L1-Cdc42 interaction. GTP-bound Cdc42 activates its downstream effectors N-WASP and Arp2/3 complex to initiate branched actin filaments assembly, which promotes dissociation of Rab11a from NPC1L1 complex and facilitates the transport of NPC1L1 towards plasma membrane by MyoVb. In vivo study with liver specific Cdc42 knockout mice confirmed that localization and function of hepatic NPC1L1 depends on Cdc42.

 

This work entitled "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" was published online in Journal of Biological Chemistry on Aug 15th, 2011.

 

This study was supported by grants from the Ministry of Science and Technology of China, the National Natural Science Foundation of China, the Chinese Academy of Sciences, and the Science and Technology Commission of Shanghai Municipality. (SIBCB)

 

AUTHOR CONTACT:

SONG Baoliang, Ph.D.

Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

Telephone: +86- 21-54921649

 

Schematic model of Cdc42 regulated transport of NPC1L1 towards plasma membrane At steady state, NPC1L1 associates with Rab11a and localizes in ERC. When cholesterol level drops, Cdc42 is activated and binds to NPC1L1 complex. The GTP-bound Cdc42 further activates N-WASP and Arp2/3 complex, which promotes the branched actin assembly. Then Rab11a gradually dissociates from NPC1L1 complex and the vesicles are transported from ERC to PM by MyoVb. When cholesterol level is high, cholesterol will induce the internalization of NPC1L1 together with cholesterol from PM (Image provided by Dr. SONG Baoliang)