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

TY - JOUR

T1 - Selective inhibition of protein secretion by abrogating receptor–coat interactions during ER export

AU - Gomez-Navarro, Natalia

AU - Maldutyte, Julija

AU - Poljak, Kristina

AU - Peak-Chew, Sew-Yeu

AU - Orme, Jonathon

AU - Bisnett, Brittany J.

AU - Lamb, Caitlin H.

AU - Boyce, Michael

AU - Gianni, Davide

AU - Miller, Elizabeth A.

PY - 2022/8/2

Y1 - 2022/8/2

N2 - 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.

AB - 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.

KW - COPII vesicles

KW - ER export

KW - membrane traffic

UR - https://www.scopus.com/pages/publications/85135214732

U2 - 10.1073/pnas.2202080119

DO - 10.1073/pnas.2202080119

M3 - Article

C2 - 35901214

SN - 0027-8424

VL - 119

JO - Proceedings of the National Academy of Sciences

JF - Proceedings of the National Academy of Sciences

IS - 31

M1 - e2202080119

ER -