VPS13D interacts with VCP/p97 and negatively regulates endoplasmic reticulum-mitochondria interactions.
VPS13D interacts with VCP/p97 and negatively regulates endoplasmic reticulum-mitochondria interactions.
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VPS13D 与 VCP/p97 相互作用并负向调节内质网与线粒体相互作用
DOI：
10.1091/mbc.e21-03-0097
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发表时间：
2021-08-01
影响因子：
3.3
通讯作者：
Ji WK
中科院分区：
文献类型：
--
作者：
Du Y;Wang J;Xiong J;Fang N;Ji WK
内质网（ER）和线粒体之间的膜接触位点（MCSs）正在成为多种细胞事件的关键枢纽，这些接触程度的改变与神经退行性疾病有关。然而，控制er -线粒体相互作用的机制迄今仍是难以捉摸的。在这里，我们证明了液泡蛋白分选相关蛋白13D （VPS13D）在er线粒体mcs的负调控中的关键作用。VPS13D抑制导致广泛的er -线粒体系固，这种表型可以通过抑制系固蛋白VAPB和PTPIP51来基本挽救。VPS13D与含valosin蛋白（VCP/p97）相互作用，控制接触处er驻留VAPB的水平。p97的稳定性需要VPS13D。功能上，VPS13D抑制导致线粒体形态、线粒体细胞分布和线粒体DNA合成的严重缺陷。总之，我们的研究结果表明VPS13D负调控er线粒体MCSs，部分通过其与VCP/p97的相互作用。
Membrane contact sites (MCSs) between the endoplasmic reticulum (ER) and mitochondria are emerging as critical hubs for diverse cellular events, and alterations in the extent of these contacts are linked to neurodegenerative diseases. However, the mechanisms that control ER–mitochondria interactions are so far elusive. Here, we demonstrate a key role of vacuolar protein sorting–associated protein 13D (VPS13D) in the negative regulation of ER–mitochondria MCSs. VPS13D suppression results in extensive ER–mitochondria tethering, a phenotype that can be substantially rescued by suppression of the tethering proteins VAPB and PTPIP51. VPS13D interacts with valosin-containing protein (VCP/p97) to control the level of ER-resident VAPB at contacts. VPS13D is required for the stability of p97. Functionally, VPS13D suppression leads to severe defects in mitochondrial morphology, mitochondrial cellular distribution, and mitochondrial DNA synthesis. Together, our results suggest that VPS13D negatively regulates the ER–mitochondria MCSs, partially through its interactions with VCP/p97.