Insufficiency of ciliary cholesterol in hereditary Zellweger syndrome

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.

Active cholesterol 20 years on

“…It is also possible that Patched is involved in the shedding of cholesterol‐rich vesicles from the cilia (see Section 5.4). How the ejected sterol returns to the cilium is not known, but peroxisomes could be involved 190 . The utilization of the small fraction of plasma membrane cholesterol that is active as the signal—and confining the ongoing pump‐leak cycle to the tiny membrane space in the cilium—would minimize the consumption of energy and avoid undermining the organization of the rest of the plasma membrane bilayer on behalf of Hedgehog signaling.…”

NBS1 I171V variant underlies individual differences in chromosomal radiosensitivity within human populations

“…RT-PCR analysis was carried out as described previously 39 . Briefly, HCT116 genome editing cells in 96-well plates were cultured in DMEM supplemented with 10% FBS for 24 h. The cells were washed with ice-cold PBS, lysed, and then, cDNAs were synthesized with reverse transcriptase from their extracted total RNA using Cells to CT Kit (ThermoFisher), in accordance with the manufacturer's protocol.…”

Peroxisomal Disorders and Their Mouse Models Point to Essential Roles of Peroxisomes for Retinal Integrity

“…Furthermore, a possible role of peroxisomes in ciliogenesis has recently been postulated by several laboratories. Several lines of evidence were provided: (i) knockdown of PEX genes partially impaired ciliogenesis, (ii) a serine-threonine kinase, NDR2, which is essential in ciliogenesis, localizes to peroxisomes, (iii) peroxisomes mediate trafficking of cholesterol into ciliary membranes [ 161 , 162 ]. Interestingly, the POS are a form of primary cilia that also contain a large amount of cholesterol in the plasma membrane and in the membranes of discs at the base [ 163 ].…”