PDF(Pubmed)
Abstract：
The mitochondria-ER-cortex anchor (MECA) forms a tripartite membrane contact site between mitochondria, the endoplasmic reticulum (ER), and the plasma membrane (PM). The core component of MECA, Num1, interacts with the PM and mitochondria via two distinct lipid-binding domains; however, the molecular mechanism by which Num1 interacts with the ER is unclear. Here, we demonstrate that Num1 contains a FFAT motif in its C-terminus that interacts with the integral ER membrane protein Scs2. While dispensable for Num1\'s functions in mitochondrial tethering and dynein anchoring, the FFAT motif is required for Num1\'s role in promoting mitochondrial division. Unexpectedly, we also reveal a novel function of MECA in regulating the distribution of phosphatidylinositol-4-phosphate (PI(4)P). Breaking Num1 association with any of the three membranes it tethers results in an accumulation of PI(4)P on the PM, likely via disrupting Sac1-mediated PI(4)P turnover. This work establishes MECA as an important regulatory hub that spatially organizes mitochondria, ER, and PM to coordinate crucial cellular functions.
摘要：
线粒体-ER-皮层锚（MECA）在线粒体之间形成了三方膜接触位点，内质网（ER），和质膜（PM）。MECA的核心组成部分，Num1通过两个不同的脂质结合域与PM和线粒体相互作用；然而，Num1与ER相互作用的分子机制尚不清楚。这里,我们证明Num1在其C末端包含一个FFAT基序，该基序与整合的ER膜蛋白Scs2相互作用。虽然Num1在线粒体系链和动力蛋白锚定中的功能是不必要的，FFAT基序是Num1在促进线粒体分裂中的作用所必需的。出乎意料的是,我们还揭示了MECA在调节磷脂酰肌醇-4-磷酸（PI（4）P）分布方面的新功能。打破Num1与它束缚的三个膜中的任何一个的关联导致PI（4）P在PM上的积累，可能是通过破坏Sac1介导的PI(4)P周转。这项工作确立了MECA作为空间组织线粒体的重要调控中心，ER,和PM来协调关键的细胞功能。
