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Elife. 2018 Sep 25;7. pii: e38839. doi: 10.7554/eLife.38839.

The cargo receptor SURF4 promotes the efficient cellular secretion of PCSK9.

Author information

1
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
2
Life Sciences Institute, University of Michigan, Ann Arbor, Michigan.
3
Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada.
4
Department of Molecular Genetics, University of Toronto, Toronto, Canada.
5
State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Center for Life Sciences, Peking University, Beijing, China.
6
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan.
7
Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan.
8
Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan.

Abstract

PCSK9 is a secreted protein that regulates plasma cholesterol levels and cardiovascular disease risk. Prior studies suggested the presence of an ER cargo receptor that recruits PCSK9 into the secretory pathway, but its identity has remained elusive. Here, we apply a novel approach that combines proximity-dependent biotinylation and proteomics together with genome-scale CRISPR screening to identify SURF4, a homologue of the yeast cargo receptor Erv29p, as a primary mediator of PCSK9 secretion in HEK293T cells. The functional contribution of SURF4 to PCSK9 secretion was confirmed with multiple independent SURF4-targeting sgRNAs, clonal SURF4-deficient cell lines, and functional rescue with SURF4 cDNA. SURF4 was found to localize to the early secretory pathway where it physically interacts with PCSK9. Deletion of SURF4 resulted in ER accumulation and decreased extracellular secretion of PCSK9. These findings support a model in which SURF4 functions as an ER cargo receptor mediating the efficient cellular secretion of PCSK9.

KEYWORDS:

PCSK9; SURF4; cargo receptor; cell biology; cholesterol; human; human biology; medicine; secretion

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