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Identification of a New Cholesterol‐Binding Site within the IFN‐γ Receptor that is Required for Signal Transduction

The cytokine interferon‐gamma (IFN‐γ) is a master regulator of innate and adaptive immunity involved in a broad array of human diseases that range from atherosclerosis to cancer. IFN‐γ exerts it signaling action by binding to a specific cell surface receptor, the IFN‐γ receptor (IFN‐γR), whose activ...

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Autores principales: Morana, Ornella, Nieto‐Garai, Jon Ander, Björkholm, Patrik, Bernardino de la Serna, Jorge, Terrones, Oihana, Arboleya, Aroa, Ciceri, Dalila, Rojo‐Bartolomé, Iratxe, Blouin, Cédric M., Lamaze, Christophe, Lorizate, Maier, Contreras, Francesc‐Xabier
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9008429/
https://www.ncbi.nlm.nih.gov/pubmed/35166455
http://dx.doi.org/10.1002/advs.202105170
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author Morana, Ornella
Nieto‐Garai, Jon Ander
Björkholm, Patrik
Bernardino de la Serna, Jorge
Terrones, Oihana
Arboleya, Aroa
Ciceri, Dalila
Rojo‐Bartolomé, Iratxe
Blouin, Cédric M.
Lamaze, Christophe
Lorizate, Maier
Contreras, Francesc‐Xabier
author_facet Morana, Ornella
Nieto‐Garai, Jon Ander
Björkholm, Patrik
Bernardino de la Serna, Jorge
Terrones, Oihana
Arboleya, Aroa
Ciceri, Dalila
Rojo‐Bartolomé, Iratxe
Blouin, Cédric M.
Lamaze, Christophe
Lorizate, Maier
Contreras, Francesc‐Xabier
author_sort Morana, Ornella
collection PubMed
description The cytokine interferon‐gamma (IFN‐γ) is a master regulator of innate and adaptive immunity involved in a broad array of human diseases that range from atherosclerosis to cancer. IFN‐γ exerts it signaling action by binding to a specific cell surface receptor, the IFN‐γ receptor (IFN‐γR), whose activation critically depends on its partition into lipid nanodomains. However, little is known about the impact of specific lipids on IFN‐γR signal transduction activity. Here, a new conserved cholesterol (chol) binding motif localized within its single transmembrane domain is identified. Through direct binding, chol drives the partition of IFN‐γR2 chains into plasma membrane lipid nanodomains, orchestrating IFN‐γR oligomerization and transmembrane signaling. Bioinformatics studies show that the signature sequence stands for a conserved chol‐binding motif presented in many mammalian membrane proteins. The discovery of chol as the molecular switch governing IFN‐γR transmembrane signaling represents a significant advance for understanding the mechanism of lipid selectivity by membrane proteins, but also for figuring out the role of lipids in modulating cell surface receptor function. Finally, this study suggests that inhibition of the chol‐IFNγR2 interaction may represent a potential therapeutic strategy for various IFN‐γ‐dependent diseases.
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spelling pubmed-90084292022-04-15 Identification of a New Cholesterol‐Binding Site within the IFN‐γ Receptor that is Required for Signal Transduction Morana, Ornella Nieto‐Garai, Jon Ander Björkholm, Patrik Bernardino de la Serna, Jorge Terrones, Oihana Arboleya, Aroa Ciceri, Dalila Rojo‐Bartolomé, Iratxe Blouin, Cédric M. Lamaze, Christophe Lorizate, Maier Contreras, Francesc‐Xabier Adv Sci (Weinh) Research Articles The cytokine interferon‐gamma (IFN‐γ) is a master regulator of innate and adaptive immunity involved in a broad array of human diseases that range from atherosclerosis to cancer. IFN‐γ exerts it signaling action by binding to a specific cell surface receptor, the IFN‐γ receptor (IFN‐γR), whose activation critically depends on its partition into lipid nanodomains. However, little is known about the impact of specific lipids on IFN‐γR signal transduction activity. Here, a new conserved cholesterol (chol) binding motif localized within its single transmembrane domain is identified. Through direct binding, chol drives the partition of IFN‐γR2 chains into plasma membrane lipid nanodomains, orchestrating IFN‐γR oligomerization and transmembrane signaling. Bioinformatics studies show that the signature sequence stands for a conserved chol‐binding motif presented in many mammalian membrane proteins. The discovery of chol as the molecular switch governing IFN‐γR transmembrane signaling represents a significant advance for understanding the mechanism of lipid selectivity by membrane proteins, but also for figuring out the role of lipids in modulating cell surface receptor function. Finally, this study suggests that inhibition of the chol‐IFNγR2 interaction may represent a potential therapeutic strategy for various IFN‐γ‐dependent diseases. John Wiley and Sons Inc. 2022-02-15 /pmc/articles/PMC9008429/ /pubmed/35166455 http://dx.doi.org/10.1002/advs.202105170 Text en © 2022 The Authors. Advanced Science published by Wiley‐VCH GmbH https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Morana, Ornella
Nieto‐Garai, Jon Ander
Björkholm, Patrik
Bernardino de la Serna, Jorge
Terrones, Oihana
Arboleya, Aroa
Ciceri, Dalila
Rojo‐Bartolomé, Iratxe
Blouin, Cédric M.
Lamaze, Christophe
Lorizate, Maier
Contreras, Francesc‐Xabier
Identification of a New Cholesterol‐Binding Site within the IFN‐γ Receptor that is Required for Signal Transduction
title Identification of a New Cholesterol‐Binding Site within the IFN‐γ Receptor that is Required for Signal Transduction
title_full Identification of a New Cholesterol‐Binding Site within the IFN‐γ Receptor that is Required for Signal Transduction
title_fullStr Identification of a New Cholesterol‐Binding Site within the IFN‐γ Receptor that is Required for Signal Transduction
title_full_unstemmed Identification of a New Cholesterol‐Binding Site within the IFN‐γ Receptor that is Required for Signal Transduction
title_short Identification of a New Cholesterol‐Binding Site within the IFN‐γ Receptor that is Required for Signal Transduction
title_sort identification of a new cholesterol‐binding site within the ifn‐γ receptor that is required for signal transduction
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9008429/
https://www.ncbi.nlm.nih.gov/pubmed/35166455
http://dx.doi.org/10.1002/advs.202105170
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