Under endoplasmic reticulum (ER) stress (ERS), cells initiate the unfolded protein response (UPR) to maintain ER homeostasis. Recent studies revealed ERS transmission between cells and tissues, by activating the cell-nonautonomous UPR in cells that do not experience ERS directly. Here, we report that ERS triggers a rapid release of ceramide independent of the UPR, but requiring the acid sphingomyelinase activity. Carried by lipoproteins, ceramide is delivered to receiving cells to induce the UPR and regulate cell functions at multiple aspects, including lipid accumulation, cell death, and cytokine production. Mechanistically, extracellular ceramide stimulates ceramide synthesis at the transcription level in receiving cells, leading to ceramide accumulation in the ER so as to reduce membrane fluidity to disrupt ER calcium homeostasis, thus activating the UPR. Sphingomyelin counterbalanced the effect of ceramide. UPR induction is the frontline response to protect cells from ceramide insult. Our study suggests ceramide-mediated ERS transmission as a universal cell–cell communication model regulating a wide range of physiological events.
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March 26 2025
Ceramide mediates cell-to-cell ER stress transmission by modulating membrane fluidity
Yazhen Huo
,
Yazhen Huo
(Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Project administration, Validation, Visualization, Writing - original draft)
1
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
, Beijing, P.R. China
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Xinlu Liu
,
Xinlu Liu
(Data curation)
1
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
, Beijing, P.R. China
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Chen Lu
,
Chen Lu
(Data curation)
1
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
, Beijing, P.R. China
2
College of Life Sciences, University of Chinese Academy of Sciences
, Beijing, P.R. China
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Tao Li
,
Tao Li
(Data curation)
1
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
, Beijing, P.R. China
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Zaili Yang
,
Zaili Yang
(Data curation)
1
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
, Beijing, P.R. China
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Fenfen Xu
,
Fenfen Xu
(Data curation)
1
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
, Beijing, P.R. China
3Division of Life Sciences and Medicine,
School of Life Sciences, University of Science and Technology of China
, Hefei, China
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Si Chen
,
Si Chen
(Data curation)
1
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
, Beijing, P.R. China
2
College of Life Sciences, University of Chinese Academy of Sciences
, Beijing, P.R. China
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Kailin Yin
,
Kailin Yin
(Resources)
1
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
, Beijing, P.R. China
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Likun Wang
(Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing)
1
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
, Beijing, P.R. China
2
College of Life Sciences, University of Chinese Academy of Sciences
, Beijing, P.R. China
Correspondence to Likun Wang: [email protected]
Search for other works by this author on:
Yazhen Huo
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Project administration, Validation, Visualization, Writing - original draft
1
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
, Beijing, P.R. China
Xinlu Liu
Data curation
1
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
, Beijing, P.R. China
Chen Lu
Data curation
1
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
, Beijing, P.R. China
2
College of Life Sciences, University of Chinese Academy of Sciences
, Beijing, P.R. China
Tao Li
Data curation
1
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
, Beijing, P.R. China
Zaili Yang
Data curation
1
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
, Beijing, P.R. China
Fenfen Xu
Data curation
1
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
, Beijing, P.R. China
3Division of Life Sciences and Medicine,
School of Life Sciences, University of Science and Technology of China
, Hefei, China
Si Chen
Data curation
1
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
, Beijing, P.R. China
2
College of Life Sciences, University of Chinese Academy of Sciences
, Beijing, P.R. China
Kailin Yin
Resources
1
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
, Beijing, P.R. China
Likun Wang
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
, Beijing, P.R. China
2
College of Life Sciences, University of Chinese Academy of Sciences
, Beijing, P.R. China
Correspondence to Likun Wang: [email protected]
Disclosures: The authors declare no competing interests exist.
Received:
May 10 2024
Revision Received:
November 28 2024
Accepted:
February 13 2025
Online ISSN: 1540-8140
Print ISSN: 0021-9525
Funding
Funder(s):
National Natural Science Foundation of China
- Award Id(s): 92354303,31770877,31900564,32170785
Funder(s):
National Key Research and Development Program of China
- Award Id(s): 2021YFA1300800,2017YFA0506400
Funder(s):
Strategic Priority Research Program of Chinese Academy Sciences
- Award Id(s): XDB37020305
Funder(s):
Chinese Academy Sciences Youth Interdisciplinary Team
- Award Id(s): JCTD-2021-07
Funder(s):
Novo Nordisk – Chinese Academy of Sciences Research Fund
- Award Id(s): NNCAS-2017-6-JRP
© 2025 Huo et al.
2025
Huo et al.
This article is distributed under the terms as described at https://rupress.org/pages/terms102024/.
J Cell Biol (2025) 224 (5): e202405060.
Article history
Received:
May 10 2024
Revision Received:
November 28 2024
Accepted:
February 13 2025
Citation
Yazhen Huo, Xinlu Liu, Chen Lu, Tao Li, Zaili Yang, Fenfen Xu, Si Chen, Kailin Yin, Likun Wang; Ceramide mediates cell-to-cell ER stress transmission by modulating membrane fluidity. J Cell Biol 5 May 2025; 224 (5): e202405060. doi: https://doi.org/10.1083/jcb.202405060
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