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

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

doi:10.1038/s41556-024-01511-x

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

Nat Cell Biol. 2024 Sep 17. doi: 10.1038/s41556-024-01511-x. Online ahead of print.

Authors

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 Lee⁷, Francesca Santoro^{8

9

10}, Jen Liou⁷, Joseph C Wu^{3

11

12}, Bianxiao Cui^{13

14}

Affiliations

¹ Department of Chemistry, Stanford University, Stanford, CA, USA.
² Wu Tsai Neurosciences Institute and ChEM-H Institute, Stanford University, Stanford, CA, USA.
³ Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
⁴ Departments of Physiology and Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
⁵ Department of Biomedical Engineering, University of North Texas, Denton, TX, USA.
⁶ Department of Chemical and Nano Engineering, University of California, San Diego, San Diego, CA, USA.
⁷ Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁸ Tissue Electronics, Istituto Italiano di Tecnologia, Naples, Italy.
⁹ Faculty of Electrical Engineering and Information Technology, RWTH Aachen University, Aachen, Germany.
¹⁰ Institute of Biological Information Processing-Bioelectronics (IBI-3), Forschungszentrum, Jülich, Germany.
¹¹ Department of Medicine, Division of Cardiology, Stanford University, Stanford, CA, USA.
¹² Department of Radiology, Stanford University, Stanford, CA, USA.
¹³ Department of Chemistry, Stanford University, Stanford, CA, USA. bcui@stanford.edu.
¹⁴ Wu Tsai Neurosciences Institute and ChEM-H Institute, Stanford University, Stanford, CA, USA. bcui@stanford.edu.

PMID: 39289582
DOI: 10.1038/s41556-024-01511-x

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.

Abstract

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