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Selective inhibition of protein secretion by abrogating receptor–coat interactions during ER export

Protein secretion is an essential process that drives cell growth, movement, and communication. Protein traffic within the secretory pathway occurs via transport intermediates that bud from one compartment and fuse with a downstream compartment to deliver their contents. Here, we explore the possibi...

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Autores principales: Gomez-Navarro, Natalia, Maldutyte, Julija, Poljak, Kristina, Peak-Chew, Sew-Yeu, Orme, Jonathon, Bisnett, Brittany J., Lamb, Caitlin H., Boyce, Michael, Gianni, Davide, Miller, Elizabeth A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9351455/
https://www.ncbi.nlm.nih.gov/pubmed/35901214
http://dx.doi.org/10.1073/pnas.2202080119
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author Gomez-Navarro, Natalia
Maldutyte, Julija
Poljak, Kristina
Peak-Chew, Sew-Yeu
Orme, Jonathon
Bisnett, Brittany J.
Lamb, Caitlin H.
Boyce, Michael
Gianni, Davide
Miller, Elizabeth A.
author_facet Gomez-Navarro, Natalia
Maldutyte, Julija
Poljak, Kristina
Peak-Chew, Sew-Yeu
Orme, Jonathon
Bisnett, Brittany J.
Lamb, Caitlin H.
Boyce, Michael
Gianni, Davide
Miller, Elizabeth A.
author_sort Gomez-Navarro, Natalia
collection PubMed
description Protein secretion is an essential process that drives cell growth, movement, and communication. Protein traffic within the secretory pathway occurs via transport intermediates that bud from one compartment and fuse with a downstream compartment to deliver their contents. Here, we explore the possibility that protein secretion can be selectively inhibited by perturbing protein–protein interactions that drive capture into transport vesicles. Human proprotein convertase subtilisin/kexin type 9 (PCSK9) is a determinant of cholesterol metabolism whose secretion is mediated by a specific cargo adaptor protein, SEC24A. We map a series of protein–protein interactions between PCSK9, its endoplasmic reticulum (ER) export receptor SURF4, and SEC24A that mediate secretion of PCSK9. We show that the interaction between SURF4 and SEC24A can be inhibited by 4-phenylbutyrate (4-PBA), a small molecule that occludes a cargo-binding domain of SEC24. This inhibition reduces secretion of PCSK9 and additional SURF4 clients that we identify by mass spectrometry, leaving other secreted cargoes unaffected. We propose that selective small-molecule inhibition of cargo recognition by SEC24 is a potential therapeutic intervention for atherosclerosis and other diseases that are modulated by secreted proteins.
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spelling pubmed-93514552022-08-05 Selective inhibition of protein secretion by abrogating receptor–coat interactions during ER export Gomez-Navarro, Natalia Maldutyte, Julija Poljak, Kristina Peak-Chew, Sew-Yeu Orme, Jonathon Bisnett, Brittany J. Lamb, Caitlin H. Boyce, Michael Gianni, Davide Miller, Elizabeth A. Proc Natl Acad Sci U S A Biological Sciences Protein secretion is an essential process that drives cell growth, movement, and communication. Protein traffic within the secretory pathway occurs via transport intermediates that bud from one compartment and fuse with a downstream compartment to deliver their contents. Here, we explore the possibility that protein secretion can be selectively inhibited by perturbing protein–protein interactions that drive capture into transport vesicles. Human proprotein convertase subtilisin/kexin type 9 (PCSK9) is a determinant of cholesterol metabolism whose secretion is mediated by a specific cargo adaptor protein, SEC24A. We map a series of protein–protein interactions between PCSK9, its endoplasmic reticulum (ER) export receptor SURF4, and SEC24A that mediate secretion of PCSK9. We show that the interaction between SURF4 and SEC24A can be inhibited by 4-phenylbutyrate (4-PBA), a small molecule that occludes a cargo-binding domain of SEC24. This inhibition reduces secretion of PCSK9 and additional SURF4 clients that we identify by mass spectrometry, leaving other secreted cargoes unaffected. We propose that selective small-molecule inhibition of cargo recognition by SEC24 is a potential therapeutic intervention for atherosclerosis and other diseases that are modulated by secreted proteins. National Academy of Sciences 2022-07-28 2022-08-02 /pmc/articles/PMC9351455/ /pubmed/35901214 http://dx.doi.org/10.1073/pnas.2202080119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Biological Sciences
Gomez-Navarro, Natalia
Maldutyte, Julija
Poljak, Kristina
Peak-Chew, Sew-Yeu
Orme, Jonathon
Bisnett, Brittany J.
Lamb, Caitlin H.
Boyce, Michael
Gianni, Davide
Miller, Elizabeth A.
Selective inhibition of protein secretion by abrogating receptor–coat interactions during ER export
title Selective inhibition of protein secretion by abrogating receptor–coat interactions during ER export
title_full Selective inhibition of protein secretion by abrogating receptor–coat interactions during ER export
title_fullStr Selective inhibition of protein secretion by abrogating receptor–coat interactions during ER export
title_full_unstemmed Selective inhibition of protein secretion by abrogating receptor–coat interactions during ER export
title_short Selective inhibition of protein secretion by abrogating receptor–coat interactions during ER export
title_sort selective inhibition of protein secretion by abrogating receptor–coat interactions during er export
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9351455/
https://www.ncbi.nlm.nih.gov/pubmed/35901214
http://dx.doi.org/10.1073/pnas.2202080119
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