Coronaviral ORF6 protein mediates inter‐organelle contacts and modulates host cell lipid flux for virus production
Coronaviral ORF6 protein mediates inter‐organelle contacts and modulates host cell lipid flux for virus production
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DOI：
10.15252/embj.2022112542
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发表时间：
2023-05
期刊：
影响因子：
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通讯作者：
Mengzhen Yue;Bing Hu;Jiajia Li;Ruifeng Chen;Zhen Yuan;Hurong Xiao;Haishuang Chang;Yaming Jiu-Yamin
中科院分区：
文献类型：
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作者：
Mengzhen Yue;Bing Hu;Jiajia Li;Ruifeng Chen;Zhen Yuan;Hurong Xiao;Haishuang Chang;Yaming Jiu-Yamin
脂滴（LD）与内质网（ER）形成细胞器间接触，促进其生物合成，而LD与线粒体的接触增强所含脂肪酸的β氧化。病毒已被证明可以利用脂滴来促进病毒的产生，但尚不清楚它们是否也调节LD与其他细胞器之间的相互作用。在这里，我们发现冠状病毒ORF 6蛋白靶向LD，并定位于线粒体-LD和ER-LD接触位点，在那里它调节LD生物发生和脂解。在分子水平上，我们发现ORF 6通过两个两亲性螺旋插入LD脂质单层。ORF 6进一步与ER膜蛋白BAP 31和USE 1相互作用以介导ER-LD接触形成。此外，ORF 6与线粒体外膜中的SAM复合物相互作用以将线粒体连接到LD。在此过程中，ORF 6促进细胞脂解和LD生物发生，以重新编程宿主细胞脂质通量并促进病毒产生。
Lipid droplets (LDs) form inter‐organelle contacts with the endoplasmic reticulum (ER) that promote their biogenesis, while LD contacts with mitochondria enhance β‐oxidation of contained fatty acids. Viruses have been shown to take advantage of lipid droplets to promote viral production, but it remains unclear whether they also modulate the interactions between LDs and other organelles. Here, we showed that coronavirus ORF6 protein targets LDs and is localized to the mitochondria‐LD and ER‐LD contact sites, where it regulates LD biogenesis and lipolysis. At the molecular level, we find that ORF6 inserts into the LD lipid monolayer via its two amphipathic helices. ORF6 further interacts with ER membrane proteins BAP31 and USE1 to mediate ER‐LDs contact formation. Additionally, ORF6 interacts with the SAM complex in the mitochondrial outer membrane to link mitochondria to LDs. In doing so, ORF6 promotes cellular lipolysis and LD biogenesis to reprogram host cell lipid flux and facilitate viral production.