The Importance of Plasma Membrane Nanodomains in Signal Transduction and Drug Repurposing

The current dogma says that nanodomains of tightly packed lipids in the plasma membrane, also known as lipid rafts, of nanometre size in resting cells aggregate to become signalling hotspots upon T cell receptor (TCR) engagement. Intriguingly, we have shown that TCR engagement is not required for a T cell signalling response - it can also be invoked by temperature or lipid composition changes which are accompanied by the aggregation of signalling molecules in lipid rafts. We have also shown that molecular pinning of membrane molecules, i.e. their transient immobilisation, for instance when surface molecules are aggregated using antibodies, causes the formation of lipid rafts where the aggregation occurs. The TCR, we have found to be located in lipid raft both in resting and activated cells. Our results demonstrate that both the formation and coalescence of lipid rafts can result in a T cell signalling response by creating an environment where signalling molecules are highly concentrated, exceeding the threshold for a signalling response. Models of how the plasma membrane biophysical rearrangement could be linked to intracellular signalling and cell topography will be presented as will examples of how drug repurposing of statins to target the biophysical organisation of the plasma membrane can combat disease.

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Publisher: REPO4EU

Publication date (Electronic, pub): 20 September 2023

Affiliations

[1 ] Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg (Sweden) ( https://ror.org/01tm6cn81)

Author information

Ingela Parmryd https://orcid.org/0000-0003-4834-3611

Article

DOI: 10.58647/REXPO.23011

SO-VID: 4fc45424-9832-4687-9da8-d9407709a38c

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Published under Creative Commons Attribution 4.0 International ( CC BY 4.0). Users are allowed to share (copy and redistribute the material in any medium or format) and adapt (remix, transform, and build upon the material for any purpose, even commercially), as long as the authors and the publisher are explicitly identified and properly acknowledged as the original source.

Conference name: RExPO23

Conference number: 2

Conference location: Stockholm, Sweden

Conference date: 25-26 October 2023

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REPO4EU

References

Adler Jeremy, Sintorn Ida-Maria, Strand Robin, Parmryd Ingela. Conventional analysis of movement on non-flat surfaces like the plasma membrane makes Brownian motion appear anomalous. Communications Biology. Vol. 2(1)2019. Springer Science and Business Media LLC. [Cross Ref]
Dinic Jelena, Ashrafzadeh Parham, Parmryd Ingela. Actin filaments attachment at the plasma membrane in live cells cause the formation of ordered lipid domains. Biochimica et Biophysica Acta (BBA) - Biomembranes. Vol. 1828(3):1102–1111. 2013. Elsevier BV. [Cross Ref]
Dinic Jelena, Riehl Astrid, Adler Jeremy, Parmryd Ingela. The T cell receptor resides in ordered plasma membrane nanodomains that aggregate upon patching of the receptor. Scientific Reports. Vol. 5(1)2015. Springer Science and Business Media LLC. [Cross Ref]
Fujimoto Toyoshi, Parmryd Ingela. Interleaflet Coupling, Pinning, and Leaflet Asymmetry—Major Players in Plasma Membrane Nanodomain Formation. Frontiers in Cell and Developmental Biology. Vol. 4:2017. Frontiers Media SA. [Cross Ref]
Gesper Astrid, Wennmalm Stefan, Hagemann Philipp, Eriksson Sven-Göran, Happel Patrick, Parmryd Ingela. Variations in Plasma Membrane Topography Can Explain Heterogenous Diffusion Coefficients Obtained by Fluorescence Correlation Spectroscopy. Frontiers in Cell and Developmental Biology. Vol. 8:2020. Frontiers Media SA. [Cross Ref]
Magee Anthony I., Adler Jeremy, Parmryd Ingela. Cold-induced coalescence of T-cell plasma membrane microdomains activates signalling pathways. Journal of Cell Science. Vol. 118(14):3141–3151. 2005. The Company of Biologists. [Cross Ref]
Mahammad Saleemulla, Dinic Jelena, Adler Jeremy, Parmryd Ingela. Limited cholesterol depletion causes aggregation of plasma membrane lipid rafts inducing T cell activation. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. Vol. 1801(6):625–634. 2010. Elsevier BV. [Cross Ref]
Santosa Ailiana, Franzén Stefan, Nåtman Jonatan, Wettermark Björn, Parmryd Ingela, Nyberg Fredrik. Protective effects of statins on COVID-19 risk, severity and fatal outcome: a nationwide Swedish cohort study. Scientific Reports. Vol. 12(1)2022. Springer Science and Business Media LLC. [Cross Ref]

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[1] Adler Jeremy, Sintorn Ida-Maria, Strand Robin, Parmryd Ingela. Conventional analysis of movement on non-flat surfaces like the plasma membrane makes Brownian motion appear anomalous. Communications Biology. Vol. 2(1)2019. Springer Science and Business Media LLC. [Cross Ref]

[2] Dinic Jelena, Ashrafzadeh Parham, Parmryd Ingela. Actin filaments attachment at the plasma membrane in live cells cause the formation of ordered lipid domains. Biochimica et Biophysica Acta (BBA) - Biomembranes. Vol. 1828(3):1102–1111. 2013. Elsevier BV. [Cross Ref]

[3] Dinic Jelena, Riehl Astrid, Adler Jeremy, Parmryd Ingela. The T cell receptor resides in ordered plasma membrane nanodomains that aggregate upon patching of the receptor. Scientific Reports. Vol. 5(1)2015. Springer Science and Business Media LLC. [Cross Ref]

[4] Fujimoto Toyoshi, Parmryd Ingela. Interleaflet Coupling, Pinning, and Leaflet Asymmetry—Major Players in Plasma Membrane Nanodomain Formation. Frontiers in Cell and Developmental Biology. Vol. 4:2017. Frontiers Media SA. [Cross Ref]

[5] Gesper Astrid, Wennmalm Stefan, Hagemann Philipp, Eriksson Sven-Göran, Happel Patrick, Parmryd Ingela. Variations in Plasma Membrane Topography Can Explain Heterogenous Diffusion Coefficients Obtained by Fluorescence Correlation Spectroscopy. Frontiers in Cell and Developmental Biology. Vol. 8:2020. Frontiers Media SA. [Cross Ref]

[6] Magee Anthony I., Adler Jeremy, Parmryd Ingela. Cold-induced coalescence of T-cell plasma membrane microdomains activates signalling pathways. Journal of Cell Science. Vol. 118(14):3141–3151. 2005. The Company of Biologists. [Cross Ref]

[7] Mahammad Saleemulla, Dinic Jelena, Adler Jeremy, Parmryd Ingela. Limited cholesterol depletion causes aggregation of plasma membrane lipid rafts inducing T cell activation. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. Vol. 1801(6):625–634. 2010. Elsevier BV. [Cross Ref]

[8] Santosa Ailiana, Franzén Stefan, Nåtman Jonatan, Wettermark Björn, Parmryd Ingela, Nyberg Fredrik. Protective effects of statins on COVID-19 risk, severity and fatal outcome: a nationwide Swedish cohort study. Scientific Reports. Vol. 12(1)2022. Springer Science and Business Media LLC. [Cross Ref]