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纤毛发生需要神经鞘脂依赖性膜和轴丝相互作用。

Ciliogenesis requires sphingolipid-dependent membrane and axoneme interaction.

机构信息

Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China.

Beijing Frontier Research Center for Biological Structure, Tsinghua University, Beijing 100084, China.

出版信息

Proc Natl Acad Sci U S A. 2022 Aug 2;119(31):e2201096119. doi: 10.1073/pnas.2201096119. Epub 2022 Jul 27.

DOI:10.1073/pnas.2201096119
PMID:35895683
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9351462/
Abstract

Cilium formation and regeneration requires new protein synthesis, but the underlying cytosolic translational reprogramming remains largely unknown. Using ribosome footprinting, we performed global translatome profiling during cilia regeneration in and uncovered that flagellar genes undergo an early transcriptional activation but late translational repression. This pattern guided our identification of sphingolipid metabolism enzymes, including serine palmitoyltransferase (SPT), as essential regulators for ciliogenesis. Cryo-electron tomography showed that ceramide loss abnormally increased the membrane-axoneme distance and generated bulged cilia. We found that ceramides interact with intraflagellar transport (IFT) particle proteins that IFT motors transport along axoneme microtubules (MTs), suggesting that ceramide-IFT particle-IFT motor-MT interactions connect the ciliary membrane with the axoneme to form rod-shaped cilia. SPT-deficient vertebrate cells were defective in ciliogenesis, and SPT mutations from patients with hereditary sensory neuropathy disrupted cilia, which could be restored by sphingolipid supplementation. These results reveal a conserved role of sphingolipid in cilium formation and link compromised sphingolipid production with ciliopathies.

摘要

纤毛的形成和再生需要新的蛋白质合成，但细胞溶质翻译重编程的基本机制在很大程度上仍不清楚。使用核糖体足迹法，我们在 和 的纤毛再生过程中进行了全局翻译组谱分析，结果表明鞭毛基因经历早期转录激活，但晚期翻译抑制。这种模式指导我们鉴定出鞘脂代谢酶，包括丝氨酸棕榈酰转移酶（SPT），作为纤毛发生的必需调节剂。冷冻电子断层扫描显示，神经酰胺缺失异常增加了膜-轴索距离，并产生了膨出的纤毛。我们发现神经酰胺与内纤毛运输（IFT）颗粒蛋白相互作用，IFT 颗粒蛋白是 IFT 马达沿轴索微管（MTs）运输的，这表明神经酰胺-IFT 颗粒-IFT 马达-MT 相互作用将纤毛膜与轴索连接起来，形成杆状纤毛。SPT 缺陷的脊椎动物细胞在纤毛发生过程中出现缺陷，遗传性感觉神经病患者的 SPT 突变破坏了纤毛，通过补充鞘脂可以恢复纤毛。这些结果揭示了鞘脂在纤毛形成中的保守作用，并将鞘脂生成受损与纤毛病联系起来。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8ca/9351462/b45001794903/pnas.2201096119fig07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8ca/9351462/18c261fefb3e/pnas.2201096119fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8ca/9351462/8ae3b55c7f76/pnas.2201096119fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8ca/9351462/40dcaad9576a/pnas.2201096119fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8ca/9351462/3ba077e0d2c0/pnas.2201096119fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8ca/9351462/047778141f4d/pnas.2201096119fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8ca/9351462/65b95c2c3ee4/pnas.2201096119fig06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8ca/9351462/b45001794903/pnas.2201096119fig07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8ca/9351462/18c261fefb3e/pnas.2201096119fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8ca/9351462/8ae3b55c7f76/pnas.2201096119fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8ca/9351462/40dcaad9576a/pnas.2201096119fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8ca/9351462/3ba077e0d2c0/pnas.2201096119fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8ca/9351462/047778141f4d/pnas.2201096119fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8ca/9351462/65b95c2c3ee4/pnas.2201096119fig06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8ca/9351462/b45001794903/pnas.2201096119fig07.jpg

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