Insufficiency of ciliary cholesterol in hereditary Zellweger syndrome.

The EMBO Journal
Tatsuo MiyamotoShinya Matsuura

Abstract

Primary cilia are antenna-like organelles on the surface of most mammalian cells that receive sonic hedgehog (Shh) signaling in embryogenesis and carcinogenesis. Cellular cholesterol functions as a direct activator of a seven-transmembrane oncoprotein called Smoothened (Smo) and thereby induces Smo accumulation on the ciliary membrane where it transduces the Shh signal. However, how cholesterol is supplied to the ciliary membrane remains unclear. Here, we report that peroxisomes are essential for the transport of cholesterol into the ciliary membrane. Zellweger syndrome (ZS) is a peroxisome-deficient hereditary disorder with several ciliopathy-related features and cells from these patients showed a reduced cholesterol level in the ciliary membrane. Reverse genetics approaches revealed that the GTP exchange factor Rabin8, the Rab GTPase Rab10, and the microtubule minus-end-directed kinesin KIFC3 form a peroxisome-associated complex to control the movement of peroxisomes along microtubules, enabling communication between peroxisomes and ciliary pocket membranes. Our findings suggest that insufficient ciliary cholesterol levels may underlie ciliopathies.

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Citations

Sep 16, 2020·Traffic·Yvonne Lange, Theodore L Steck
Nov 4, 2020·Cellular and Molecular Life Sciences : CMLS·Christian Covill-CookeJosef T Kittler
Jan 10, 2021·Science China. Life Sciences·Jie LuoBao-Liang Song
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Mar 28, 2021·Pharmacology & Therapeutics·Max Duong PhuMelanie Philipp
May 1, 2021·International Journal of Molecular Sciences·Yannick DasMyriam Baes
Jun 30, 2021·Trends in Cell Biology·Marta Lovera, Jens Lüders

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Datasets Mentioned

BETA
GM17398

Methods Mentioned

BETA
GTPase
scanning
electron microscopy
confocal microscopy
immunoprecipitation
PCR
transfection
genotyping
gene knockout
Assay

Software Mentioned

Amira
Imaris
Auto Slice and View
ImageJ
ZEN
STAR

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