NPC intracellular cholesterol transporter 1

Definition:

Intracellular cholesterol transporter which acts in concert with NPC2 and plays an important role in the egress of cholesterol from the endosomal/lysosomal compartment. Unesterified cholesterol that has been released from LDLs in the lumen of the late endosomes/lysosomes is transferred by NPC2 to the cholesterol-binding pocket in the N-terminal domain of NPC1. Cholesterol binds to NPC1 with the hydroxyl group buried in the binding pocket. Binds oxysterol with higher affinity than cholesterol. May play a role in vesicular trafficking in glia, a process that may be crucial for maintaining the structural and functional integrity of nerve terminals (Probable). Inhibits cholesterol-mediated mTORC1 activation throught its interaction with SLC38A9.; (Microbial infection) Acts as an endosomal entry receptor for ebolavirus.

References:

[1]. J P Davies, et al. Topological analysis of Niemann-Pick C1 protein reveals that the membrane orientation of the putative sterol-sensing domain is identical to those of 3-hydroxy-3-methylglutaryl-CoA reductase and sterol regulatory element binding protein cleavage-activating protein. J Biol Chem. 2000 Aug 11;275(32):24367-74. [Content Brief]

[2]. Jan E Carette, et al. Ebola virus entry requires the cholesterol transporter Niemann-Pick C1. Nature. 2011 Aug 24;477(7364):340-3. [Content Brief]

[3]. E D Carstea, et al. Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science. 1997 Jul 11;277(5323):228-31. [Content Brief]

[4]. Makoto Kuroda, et al. Interaction between TIM-1 and NPC1 Is Important for Cellular Entry of Ebola Virus. J Virol. 2015 Jun;89(12):6481-93. [Content Brief]

[5]. Xin Gong, et al. Structural Insights into the Niemann-Pick C1 (NPC1)-Mediated Cholesterol Transfer and Ebola Infection. Cell. 2016 Jun 2;165(6):1467-1478. [Content Brief]

[6]. Brian M Castellano, et al. Lysosomal cholesterol activates mTORC1 via an SLC38A9-Niemann-Pick C1 signaling complex. Science. 2017 Mar 24;355(6331):1306-1311. [Content Brief]

[7]. Titta S Blom, et al. Defective endocytic trafficking of NPC1 and NPC2 underlying infantile Niemann-Pick type C disease. Hum Mol Genet. 2003 Feb 1;12(3):257-72. [Content Brief]

[8]. Anna Bruchez, et al. MHC class II transactivator CIITA induces cell resistance to Ebola virus and SARS-like coronaviruses. Science. 2020 Oct 9;370(6513):241-247. [Content Brief]

[9]. Hyock Joo Kwon, et al. Structure of N-terminal domain of NPC1 reveals distinct subdomains for binding and transfer of cholesterol. Cell. 2009 Jun 26;137(7):1213-24. [Content Brief]

[10]. H Watari, et al. Niemann-Pick C1 protein: obligatory roles for N-terminal domains and lysosomal targeting in cholesterol mobilization. Proc Natl Acad Sci U S A. 1999 Feb 2;96(3):805-10. [Content Brief]

[11]. Rodney E Infante, et al. NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a step in cholesterol egress from lysosomes. Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15287-92. [Content Brief]

[12]. Xiaochun Li, et al. 3.3 Å structure of Niemann-Pick C1 protein reveals insights into the function of the C-terminal luminal domain in cholesterol transport. Proc Natl Acad Sci U S A. 2017 Aug 22;114(34):9116-9121. [Content Brief]

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