TMEM135 regulates primary ciliogenesis through modulation of intracellular cholesterol distribution. (11th March 2020)

• Record Type: Journal Article
• Authors: Maharjan, Yunash; Lee, Joon No; Kwak, Seong Ae; Dutta, Raghbendra Kumar; Park, Channy; Choe, Seong‐Kyu; Park, Raekil
• Is Part Of: EMBO reports. Volume 21:Number 5(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-03-11
• Subjects: IFT20 -- intracellular cholesterol transport -- peroxisome -- primary cilia -- Rab8 -- TMEM135; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201948901
• Languages: English
• ISSNs: 1469-221X

Abstract

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 cholesterol distribution on impairing Rab8 function and primary ciliogenesis. Synopsis: This study reveals that depletion of TMEM135 from peroxisome leads to lysosomal cholesterol accumulation, which impairs Rab8 mediated primary ciliogenesis. Depletion of peroxisome protein TMEM135 disrupts the intracellular cholesterol distribution. Depletion of TMEM135 blunts Rab8 trafficking and IFT20 trafficking to the centrioles. Impaired Rab8 function is closely associated with lysosomal cholesterol accumulation. Water‐soluble cholesterol rescues Rab8 trafficking and ciliogenesis in TMEM135 depleted cells. Abstract : This study reveals that depletion of TMEM135 from peroxisome leads to lysosomal cholesterol accumulation, which impairs Rab8 mediated primary ciliogenesis.