Membrane Curvature Promotes ER-PM Contact Formation via Junctophilin-EHD Interactions
Year: 2024
Type: preprint
Abstract: Contact sites between the endoplasmic reticulum (ER) and the 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 (T-tubules), we hypothesize that the 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, while 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 the MORN motifs of junctophilins can independently bind 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 (EHDs), that interact with the MORN_LCR motifs and facilitate junctophilins' preferential tethering to curved PM. These findings highlight the pivotal role of PM curvature in the formation of ER-PM contacts in cardiomyocytes and unveil a novel mechanism for the spatial regulation of ER-PM contacts through PM curvature modulation.
Authors: 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
Institutions: Stanford University, Medical College of Wisconsin, Stanford Cardiovascular Institute, University of North Texas, University of California San Diego, The University of Texas Southwestern Medical Center, Forschungszentrum Jülich, Italian Institute of Technology, RWTH Aachen University, Stanford Medicine
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: green
Awards: Homeostatic Regulation of PIP2-Calcium Signaling, Single-cell Multi-omic Profiling of Drug Responses Using Pooled iPSC-CM Differentiation, Human Induced Pluripotent Stem Cells for Cardiovascular Disease Modeling, Label-free Optical Recording of Neuroelectric Activities, Stanford ChEM-H Chemistry/Biology Interface Predoctoral Training Program, Elucidating Anthracycline-Induced Cell Type-Specific Cardiovascular Toxicity with CRISPRi/a Screens, Nanoscale probes for sensing molecular functions in live cells, An electrophysiology platform that enables robust, scalable and long-term intracellular recording of cardiomyocytes
OpenAlex ID: W4400212359