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Insufficiency of ciliary cholesterol in hereditary Zellweger syndrome
Author(s) -
Miyamoto Tatsuo,
Hosoba Kosuke,
Itabashi Takeshi,
Iwane Atsuko H,
Akutsu Silvia Natsuko,
Ochiai Hiroshi,
Saito Yumiko,
Yamamoto Takashi,
Matsuura Shinya
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019103499
Subject(s) - zellweger syndrome , biology , cholesterol , adrenal insufficiency , endocrinology , medicine , genetics , gene , peroxisome
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 GTP ase Rab10, and the microtubule minus‐end‐directed kinesin KIFC 3 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.