Functional coupling between TRPV4 channel and TMEM16F modulates human trophoblast fusion

  1. Yang Zhang
  2. Pengfei Liang
  3. Liheng Yang
  4. Ke Zoe Shan
  5. Liping Feng
  6. Yong Chen
  7. Wolfgang Liedtke
  8. Carolyn B Coyne
  9. Huanghe Yang  Is a corresponding author
  1. Duke University, United States
  2. Regeneron Pharmaceuticals, United States

Abstract

TMEM16F, a Ca2+-activated phospholipid scramblase (CaPLSase), is critical for placental trophoblast syncytialization, HIV infection, and SARS-CoV2-mediated syncytialization, however, how TMEM16F is activated during cell fusion is unclear. Here, using trophoblasts as a model for cell fusion, we demonstrate that Ca2+ influx through the Ca2+ permeable transient receptor potential vanilloid channel TRPV4 is critical for TMEM16F activation and plays a role in subsequent human trophoblast fusion. GSK1016790A, a TRPV4 specific agonist, robustly activates TMEM16F in trophoblasts. We also show that TRPV4 and TMEM16F are functionally coupled within Ca2+ microdomains in a human trophoblast cell line using patch clamp electrophysiology. Pharmacological inhibition or gene silencing of TRPV4 hinders TMEM16F activation and subsequent trophoblast syncytialization. Our study uncovers the functional expression of TRPV4 and one of the physiological activation mechanisms of TMEM16F in human trophoblasts, thus providing us with novel strategies to regulate CaPLSase activity as a critical checkpoint of physiologically- and disease-relevant cell fusion events.

Data availability

All study data are included in the article and/or supporting information. All the numerical data can be found in the associated 'Source data' files for each figures. The MATLAB code supporting the present study is available at GitHub https://github.com/YZ299/matlabcode/blob/main/matlabcode.m.

Article and author information

Author details

  1. Yang Zhang

    Department of Biochemistry, Duke University, Durham, United States
    Competing interests
    No competing interests declared.
  2. Pengfei Liang

    Department of Biochemistry, Duke University, Durham, United States
    Competing interests
    No competing interests declared.
  3. Liheng Yang

    Department of Molecular Genetics and Microbiology, Duke University, Durham, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6842-086X
  4. Ke Zoe Shan

    Department of Biochemistry, Duke University, Durham, United States
    Competing interests
    No competing interests declared.
  5. Liping Feng

    Department of Obstetrics and Gynecology, Duke University, Durham, United States
    Competing interests
    No competing interests declared.
  6. Yong Chen

    Department of Neurology, Duke University, Durham, United States
    Competing interests
    No competing interests declared.
  7. Wolfgang Liedtke

    Regeneron Pharmaceuticals, Tarrytown, United States
    Competing interests
    Wolfgang Liedtke, is affiliated with Regeneron Pharmaceuticals. The author has no financial interests to declare.
  8. Carolyn B Coyne

    Department of Molecular Genetics and Microbiology, Duke University, Durham, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1884-6309
  9. Huanghe Yang

    Department of Biochemistry, Duke University, Durham, United States
    For correspondence
    huanghe.yang@duke.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9521-9328

Funding

National Institutes of Health (DP2GM126898)

  • Huanghe Yang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Andrés Jara-Oseguera, The University of Texas at Austin, United States

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#A086-21-04) of Duke University.

Human subjects: Placental tissues were collected under the Institutional Review Board approval (IRB# PRO00014627 of Duke University and XHEC-C-2018-089 of Xinhua Hospital). Informed consent was obtained following the IRBs.

Version history

  1. Preprint posted: December 12, 2021 (view preprint)
  2. Received: March 22, 2022
  3. Accepted: June 5, 2022
  4. Accepted Manuscript published: June 7, 2022 (version 1)
  5. Version of Record published: June 27, 2022 (version 2)
  6. Version of Record updated: June 28, 2022 (version 3)

Copyright

© 2022, Zhang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Yang Zhang
  2. Pengfei Liang
  3. Liheng Yang
  4. Ke Zoe Shan
  5. Liping Feng
  6. Yong Chen
  7. Wolfgang Liedtke
  8. Carolyn B Coyne
  9. Huanghe Yang
(2022)
Functional coupling between TRPV4 channel and TMEM16F modulates human trophoblast fusion
eLife 11:e78840.
https://doi.org/10.7554/eLife.78840

Share this article

https://doi.org/10.7554/eLife.78840

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