期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：31
DOI：10.1073/pnas.2202080119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
This study investigates the fundamental cellular process of protein secretion, focusing on the selectivity of this process and how it can be modulated by small-molecule inhibition. We map the protein–protein interaction network that drives secretion via the endoplasmic reticulum (ER) export receptor SURF4. We show that interaction with the COPII cargo adaptor, SEC24, is mediated by a binding pocket that can be occluded by a small-molecule inhibitor. Together, our findings support the exciting prospect that secretion of select proteins can be modulated by inhibition of the protein–protein interaction network that promotes capture into COPII vesicles.
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.
