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TMEM135 通过调节细胞内胆固醇分布调控初级纤毛生成。

TMEM135 regulates primary ciliogenesis through modulation of intracellular cholesterol distribution.

机构信息

Department of Biomedical Science & Engineering, Gwangju Institute of Science & Technology, Gwangju, Korea.

Department of Microbiology and Center for Metabolic Function Regulation, Wonkwang University School of Medicine, Iksan, Korea.

出版信息

EMBO Rep. 2020 May 6;21(5):e48901. doi: 10.15252/embr.201948901. Epub 2020 Mar 11.

DOI:10.15252/embr.201948901
PMID:32157776
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7202201/
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.

摘要

最近的证据表明，尼曼-匹克 C1 型溶酶体胆固醇积累与初级纤毛发生相关的异常有关。在这里，我们报告说，TMEM135 耗竭期间溶酶体胆固醇积累引起的细胞内胆固醇分布紊乱与纤毛发生受损密切相关。TMEM135 耗竭不影响基体的形成和纤毛过渡区。TMEM135 耗竭严重阻碍 Rab8 向中心体的运输，而不影响 Rab11 和 Rabin8（Rab8 激活的上游调节剂）在中心体的定位。尽管 TMEM135 耗竭阻止了 IFT20 在中心体处的增强定位，但纤毛小泡的形成不受影响。此外，IFT20 在中心体处的增强定位依赖于 Rab8 的激活。用与环糊精复合的胆固醇进行补充可挽救 Rab8 向中心体的运输和 Rab8 的激活，从而恢复 TMEM135 耗竭细胞中的初级纤毛发生。综上所述，我们的数据表明，TMEM135 耗竭阻止了纤毛小泡的伸长，这是 Rab8 功能受损的特征。我们的研究因此揭示了错误的细胞内胆固醇分布对破坏 Rab8 功能和初级纤毛发生的先前未被描述的影响。

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