美国斯坦福大学Bianxiao Cui小组发现，质膜的曲率调控与内质网接触的形成。该项研究成果于2024年9月17日在线发表在《自然—细胞生物学》杂志上。

受心肌细胞中观察到的现象启发，在心肌细胞中，内质网（ER）-质膜（PM）接触位点集中于称为横小管的管状PM内陷，研究人员假设PM曲率在ER-PM接触形成中起作用。通过精确控制PM内陷，研究人员展示了PM曲率在局部诱导心肌细胞中ER-PM接触形成的作用。有趣的是，ER-PM连接蛋白家族中的亲联蛋白家族在这一过程中起到了关键作用，而广泛表达的延伸突触蛋白2并未表现出对PM曲率的偏好。

在机制层面，研究人员发现亲联蛋白的低复杂度区域（LCR）和膜占据与识别界面（MORN）基序可以独立结合PM，但LCR和MORN基序都需要共同作用以靶向PM曲率。

通过研究亲联蛋白的相互作用组，研究人员鉴定出一类感知曲率的蛋白家族——Eps15同源域蛋白，这些蛋白与MORN_LCR基序相互作用并促进亲联蛋白优先结合于弯曲的PM。

这些发现突显了PM曲率在心肌细胞中ER-PM接触形成中的关键作用，并揭示了通过PM曲率调控ER-PM接触空间分布的机制。

研究人员表示，ER与PM之间的接触位点在钙调节和脂质稳态中发挥着关键作用。尽管它们具有重要性，调控这些接触位点在PM上空间分布的因素仍不清楚。

附：英文原文

Title: Plasma membrane curvature regulates the formation of contacts with the endoplasmic reticulum

Author: Yang, Yang, Valencia, Luis A., Lu, Chih-Hao, Nakamoto, Melissa L., Tsai, Ching-Ting, Liu, Chun, Yang, Huaxiao, Zhang, Wei, Jahed, Zeinab, Lee, Wan-Ru, Santoro, Francesca, Liou, Jen, Wu, Joseph C., Cui, Bianxiao

Issue&Volume: 2024-09-17

Abstract: Contact sites between the endoplasmic reticulum (ER) and plasma membrane (PM) play a crucial role in governing calcium regulation and lipid homeostasis. Despite their significance, the factors regulating their spatial distribution on the PM remain elusive. Inspired by observations in cardiomyocytes, where ER–PM contact sites concentrate on tubular PM invaginations known as transverse tubules, we hypothesize that PM curvature plays a role in ER–PM contact formation. Through precise control of PM invaginations, we show that PM curvatures locally induce the formation of ER–PM contacts in cardiomyocytes. Intriguingly, the junctophilin family of ER–PM tethering proteins, specifically expressed in excitable cells, is the key player in this process, whereas the ubiquitously expressed extended synaptotagmin-2 does not show a preference for PM curvature. At the mechanistic level, we find that the low-complexity region (LCR) and membrane occupation and recognition nexus (MORN) motifs of junctophilins can bind independently to the PM, but both the LCR and MORN motifs are required for targeting PM curvatures. By examining the junctophilin interactome, we identify a family of curvature-sensing proteins—Eps15 homology domain-containing proteins—that interact with the MORN_LCR motifs and facilitate the preferential tethering of junctophilins to curved PM. These findings highlight the pivotal role of PM curvature in the formation of ER–PM contacts in cardiomyocytes and unveil a mechanism for the spatial regulation of ER–PM contacts through PM curvature modulation.

DOI: 10.1038/s41556-024-01511-x

Source: https://www.nature.com/articles/s41556-024-01511-x