Plasma membrane curvature regulates the formation of contacts with the endoplasmic reticulum,Nature Cell Biology

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Plasma membrane curvature regulates the formation of contacts with the endoplasmic reticulum
Nature Cell Biology ( IF 17.3 ) Pub Date : 2024-09-17 , DOI: 10.1038/s41556-024-01511-x
Yang Yang _{1,

2} , Luis A Valencia _{1,

2} , Chih-Hao Lu _{1,

2} , Melissa L Nakamoto _{1,

2} , Ching-Ting Tsai _{1,

2} , Chun Liu _{3,

4} , Huaxiao Yang _{3,

5} , Wei Zhang _{1,

2} , Zeinab Jahed _{1,

6} , Wan-Ru Lee ₇ , Francesca Santoro _{8,

9,

10} , Jen Liou ₇ , Joseph C Wu _{3,

11,

12} , Bianxiao Cui _{1,

2}

Affiliation

Department of Chemistry, Stanford University, Stanford, CA, USA.
Wu Tsai Neurosciences Institute and ChEM-H Institute, Stanford University, Stanford, CA, USA.
Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
Departments of Physiology and Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
Department of Biomedical Engineering, University of North Texas, Denton, TX, USA.
Department of Chemical and Nano Engineering, University of California, San Diego, San Diego, CA, USA.
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Tissue Electronics, Istituto Italiano di Tecnologia, Naples, Italy.
Faculty of Electrical Engineering and Information Technology, RWTH Aachen University, Aachen, Germany.
Institute of Biological Information Processing-Bioelectronics (IBI-3), Forschungszentrum, Jülich, Germany.
Department of Medicine, Division of Cardiology, Stanford University, Stanford, CA, USA.
Department of Radiology, Stanford University, Stanford, CA, USA.

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.

中文翻译：

质膜曲率调节与内质网接触的形成

内质网（ER）和质膜（PM）之间的接触位点在控制钙调节和脂质稳态中起着至关重要的作用。尽管它们很重要，但调节它们在 PM 上空间分布的因素仍然难以捉摸。受心肌细胞观察的启发，其中 ER-PM 接触位点集中在称为横管的肾小管 PM 内陷，我们假设 PM 曲率在 ER-PM 接触形成中发挥作用。通过精确控制 PM 内陷，我们表明 PM 曲率局部诱导心肌细胞中 ER-PM 接触的形成。有趣的是，ER-PM 栓系蛋白的 junctophilin 家族，特别是在可兴奋细胞中表达，是这一过程中的关键参与者，而普遍表达的延伸突触结合蛋白-2 没有表现出对 PM 曲率的偏好。在机制水平上，我们发现嗜酸菌素的低复杂性区域（LCR）和膜占据与识别联系（MORN）基序可以独立与 PM 结合，但 LCR 和 MORN 基序都是靶向 PM 曲率所必需的。通过检查邻糖蛋白相互作用组，我们鉴定了一个曲率感应蛋白家族 - 包含 Eps15 同源结构域的蛋白质 - 它们与 MORN_LCR 基序相互作用并促进 junctophilin 与弯曲 PM 的优先拴系。这些发现强调了 PM 曲率在心肌细胞中 ER-PM 接触形成中的关键作用，并揭示了一种通过 PM 曲率调节对 ER-PM 接触进行空间调节的机制。

更新日期：2024-09-17

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