Premium
TMEM135 regulates primary ciliogenesis through modulation of intracellular cholesterol distribution
Author(s) -
Maharjan Yunash,
Lee Joon No,
Kwak Seong Ae,
Dutta Raghbendra Kumar,
Park Channy,
Choe SeongKyu,
Park Raekil
Publication year - 2020
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201948901
Subject(s) - ciliogenesis , cilium , microbiology and biotechnology , biology , centriole , intracellular , basal body , microtubule , biochemistry , flagellum , gene
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 TMEM 135 depletion is closely associated with impaired ciliogenesis. TMEM 135 depletion does not affect the formation of the basal body and the ciliary transition zone. TMEM 135 depletion severely blunts Rab8 trafficking to the centrioles without affecting the centriolar localization of Rab11 and Rabin8, the upstream regulators of Rab8 activation. Although TMEM 135 depletion prevents enhanced IFT 20 localization at the centrioles, ciliary vesicle formation is not affected. Furthermore, enhanced IFT 20 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 TMEM 135‐depleted cells. Taken together, our data suggest that TMEM 135 depletion prevents ciliary vesicle elongation, a characteristic of impaired Rab8 function. Our study thus reveals a previously uncharacterized effect of erroneous intracellular cholesterol distribution on impairing Rab8 function and primary ciliogenesis.