The p97-UBXD8 complex regulates ER-Mitochondria contact sites by altering membrane lipid saturation and composition.
The p97-UBXD8 complex regulates ER-Mitochondria contact sites by altering membrane lipid saturation and composition.
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DOI：
10.1038/s41467-023-36298-2
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发表时间：
2023-02-06
影响因子：
16.6
通讯作者：
Raman, Malavika
中科院分区：
文献类型：
--
作者：
Ganji, Rakesh;Paulo, Joao A.;Xi, Yuecheng;Kline, Ian;Zhu, Jiang;Clemen, Christoph S.;Weihl, Conrad C.;Purdy, John G.;Gygi, Steve P.;Raman, Malavika
内质网（ER）和线粒体膜在ER-线粒体接触位点（ERMCS）处的紧密联系是关键细胞过程（特别是脂质合成）的平台。如何接触重塑和改变接触对脂质代谢的影响仍然知之甚少。我们发现，p97 AAA-ATP酶和它的适配器ubiquitin-X域适配器8（UBXD 8）调节ERMCS。p97-UBXD 8复合物定位于接触，其损失以依赖于p97催化活性的方式增加接触。ERMCS的定量蛋白质组学和脂质组学证实了调节脂质代谢的蛋白质的改变以及UBXD 8缺失后膜脂质饱和度的显著变化。p97-UBXD 8的缺失通过SREBP 1和脂质去饱和酶SCD 1增加膜脂质饱和度。异常接触可以通过不饱和脂肪酸或SCD 1的过度表达来挽救。我们发现，SREBP 1-SCD 1通路在p97突变导致神经退行性变的小鼠大脑中受到负面影响。我们建议，接触是非常敏感的改变膜脂质成分和饱和度。细胞器间的接触是几个关键的细胞过程，如脂质合成的枢纽。Ganji等人在本文中表明，p97-UBXD 8复合物通过调节膜脂质组成和饱和度来调节接触。
The intimate association between the endoplasmic reticulum (ER) and mitochondrial membranes at ER-Mitochondria contact sites (ERMCS) is a platform for critical cellular processes, particularly lipid synthesis. How contacts are remodeled and the impact of altered contacts on lipid metabolism remains poorly understood. We show that the p97 AAA-ATPase and its adaptor ubiquitin-X domain adaptor 8 (UBXD8) regulate ERMCS. The p97-UBXD8 complex localizes to contacts and its loss increases contacts in a manner that is dependent on p97 catalytic activity. Quantitative proteomics and lipidomics of ERMCS demonstrates alterations in proteins regulating lipid metabolism and a significant change in membrane lipid saturation upon UBXD8 deletion. Loss of p97-UBXD8 increased membrane lipid saturation via SREBP1 and the lipid desaturase SCD1. Aberrant contacts can be rescued by unsaturated fatty acids or overexpression of SCD1. We find that the SREBP1-SCD1 pathway is negatively impacted in the brains of mice with p97 mutations that cause neurodegeneration. We propose that contacts are exquisitely sensitive to alterations to membrane lipid composition and saturation. Inter-organellar contacts are hubs for several critical cellular processes, such as lipid synthesis. Here Ganji et al. show that the p97-UBXD8 complex modulates contacts by regulating membrane lipid composition and saturation.
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DOI：
10.1016/j.jbc.2021.100731
发表时间：
2021-01
期刊：
The Journal of biological chemistry
影响因子：
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作者：
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通讯作者：
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