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

Natalia Gomez-Navarro, Julija Maldutyte, Kristina Poljak, Sew-Yeu Peak-Chew, Jonathon Orme, Brittany J. Bisnett, Caitlin H. Lamb, Michael Boyce, Davide Gianni, Elizabeth A. Miller

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)
16 Downloads (Pure)

Abstract

Protein secretion is an essential process that drives cell growth, movement, and commu-nication. Protein traffic within the secretory pathway occurs via transport intermediatesthat bud from one compartment and fuse with a downstream compartment to delivertheir contents. Here, we explore the possibility that protein secretion can be selectivelyinhibited by perturbing protein–protein interactions that drive capture into transportvesicles. Human proprotein convertase subtilisin/kexin type 9 (PCSK9) is a determi-nant of cholesterol metabolism whose secretion is mediated by a specific cargo adaptorprotein, SEC24A. We map a series of protein–protein interactions between PCSK9, itsendoplasmic reticulum (ER) export receptor SURF4, and SEC24A that mediate secre-tion of PCSK9. We show that the interaction between SURF4 and SEC24A can beinhibited by 4-phenylbutyrate (4-PBA), a small molecule that occludes a cargo-bindingdomain of SEC24. This inhibition reduces secretion of PCSK9 and additional SURF4clients that we identify by mass spectrometry, leaving other secreted cargoes unaffected.We propose that selective small-molecule inhibition of cargo recognition by SEC24 is apotential therapeutic intervention for atherosclerosis and other diseases that are modu-lated by secreted proteins.
Original languageEnglish
Article numbere2202080119
Number of pages11
JournalProceedings of the National Academy of Sciences
Volume119
Issue number31
Early online date28 Jul 2022
DOIs
Publication statusPublished - 2 Aug 2022

Keywords

  • COPII vesicles
  • ER export
  • membrane traffic

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