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  3. Using an ER-specific optogenetic mechanostimulator to understand the mechanosensitivity of the endoplasmic reticulum

Using an ER-specific optogenetic mechanostimulator to understand the mechanosensitivity of the endoplasmic reticulum

  • Dev Cell. 2024 Apr 1:S1534-5807(24)00180-1. doi: 10.1016/j.devcel.2024.03.014.
Yutong Song 1,  Zhihao Zhao 1,  Linyu Xu 1,  Peiyuan Huang 1,  Jiayang Gao 2,  Jingxuan Li 3,  Xuejie Wang 4,  Yiren Zhou 4,  Jinhui Wang 4,  Wenting Zhao 5,  Likun Wang 6,  Chaogu Zheng 7,  Bo Gao 3,  Liwen Jiang 2,  Kai Liu 8,  Yusong Guo 4,  Xiaoqiang Yao 3,  Liting Duan 9
Affiliations

Affiliations

  • 1 Department of Biomedical Engineering, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR 999077, China.
  • 2 School of Life Sciences, Centre for Cell & Developmental Biology and State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR 999077, China.
  • 3 School of Biomedical Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR 999077, China.
  • 4 Division of Life Science, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Kowloon, Hong Kong SAR 999077, China.
  • 5 School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore 637457, Singapore.
  • 6 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
  • 7 School of Biological Sciences, Faculty of Science, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR 999077, China.
  • 8 Division of Life Science, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Kowloon, Hong Kong SAR 999077, China; Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Kowloon, Hong Kong SAR 999077, China.
  • 9 Department of Biomedical Engineering, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR 999077, China. Electronic address: ltduan@cuhk.edu.hk.
PMID: 38569547 DOI: 10.1016/j.devcel.2024.03.014
Abstract

The ability of cells to perceive and respond to mechanical cues is essential for numerous biological activities. Emerging evidence indicates important contributions of organelles to cellular mechanosensitivity and mechanotransduction. However, whether and how the endoplasmic reticulum (ER) senses and reacts to mechanical forces remains elusive. To fill the knowledge gap, after developing a light-inducible ER-specific mechanostimulator (LIMER), we identify that mechanostimulation of ER elicits a transient, rapid efflux of CA2+ from ER in monkey kidney COS-7 cells, which is dependent on the cation channels transient receptor potential cation channel, subfamily V, member 1 (TRPV1) and polycystin-2 (PKD2) in an additive manner. This ER CA2+ release can be repeatedly stimulated and tuned by varying the intensity and duration of force application. Moreover, ER-specific mechanostimulation inhibits ER-to-Golgi trafficking. Sustained mechanostimuli increase the levels of binding-immunoglobulin protein (BiP) expression and phosphorylated eIF2α, two markers for ER stress. Our results provide direct evidence for ER mechanosensitivity and tight mechanoregulation of ER functions, placing ER as an important player on the intricate map of cellular mechanotransduction.

Keywords

ER Ca(2+) signaling; ER mechanostimulator; ER stress; ER-Golgi transport; light-gated hetero-dimerization; optical dimerizer; optogenetics; organelle mechanobiology.

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