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First published online June 20, 2006

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Low cholesterol recipe for Niemann-Pick proteins

Niemann-Pick disease type C is an inherited lipid storage disorder in which disruption of cellular cholesterol trafficking leads to accumulation of cholesterol in endosomes. It is caused by defects in the late-endosomal membrane glycoprotein NPC1, which contains a sterol-sensing domain, or in the soluble lysosomal protein NPC2, which contains a cholesterol-binding domain. On p. 2643, Haruaki Ninomiya and co-authors describe how cholesterol might regulate NPC1 function. Depletion of cellular cholesterol, they report, facilitates ubiquitylation of NPC1. This response is lost in NPC1 mutants that contain a non-functional sterol-sensing domain or lack an endosomal-targeting motif. The authors then show that SKD1, a component of the ESCRT complex that takes ubiquitylated proteins to the lysosome, associates with NPC1 only in cells depleted of cholesterol. Finally, they show that, in cells that lack NPC2, NPC1 is ubiquitylated regardless of cholesterol levels. The authors propose, therefore, that endosomal cholesterol levels control the intracellular sorting of NPC1 by controlling its ubiquitylation, and that NPC2 somehow extracts membrane-bound cholesterol so that NPC1 can detect it.

Related articles in JCS:

Cholesterol depletion facilitates ubiquitylation of NPC1 and its association with SKD1/Vps4

Yuki Ohsaki, Yuko Sugimoto, Michitaka Suzuki, Hiroshi Hosokawa, Tamotsu Yoshimori, Joanna P. Davies, Yiannis A. Ioannou, Marie T. Vanier, Kousaku Ohno, and Haruaki Ninomiya
JCS 2006 119: 2643-2653. [Abstract] [Full Text]  

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in JCS Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Search for Related Content