TMEM135 regulates primary ciliogenesis through modulation of intracellular cholesterol distribution.

EMBO Reports
Yunash MaharjanRaekil Park

Abstract

Recent evidence has linked the lysosomal cholesterol accumulation in Niemann-Pick type C1 with anomalies associated with primary ciliogenesis. Here, we report that perturbed intracellular cholesterol distribution imposed by lysosomal cholesterol accumulation during TMEM135 depletion is closely associated with impaired ciliogenesis. TMEM135 depletion does not affect the formation of the basal body and the ciliary transition zone. TMEM135 depletion severely blunts Rab8 trafficking to the centrioles without affecting the centriolar localization of Rab11 and Rabin8, the upstream regulators of Rab8 activation. Although TMEM135 depletion prevents enhanced IFT20 localization at the centrioles, ciliary vesicle formation is not affected. Furthermore, enhanced IFT20 localization at the centrioles is dependent on Rab8 activation. Supplementation of cholesterol in complex with cyclodextrin rescues Rab8 trafficking to the centrioles and Rab8 activation, thereby recovering primary ciliogenesis in TMEM135-depleted cells. Taken together, our data suggest that TMEM135 depletion prevents ciliary vesicle elongation, a characteristic of impaired Rab8 function. Our study thus reveals a previously uncharacterized effect of erroneous intracellular ch...Continue Reading

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Citations

Jan 10, 2021·Science China. Life Sciences·Jie LuoBao-Liang Song
Jan 29, 2021·Frontiers in Cell and Developmental Biology·Serhii ChornyiHans R Waterham
Jul 28, 2020·Biochimica Et Biophysica Acta. Molecular Cell Research·Beatriz S C SilvaMichael Schrader
Oct 17, 2020·Investigative Ophthalmology & Visual Science·Michael LandowskiAkihiro Ikeda

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Methods Mentioned

BETA
cleavage assay
nuclear translocation
GTPase
pull down
transfection
nucleotide exchange
immunoprecipitation
Assay
Crosslink Immunoprecipitation
electrophoresis

Software Mentioned

ImageJ

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