The cargo receptor SURF4 promotes the efficient cellular secretion of PCSK9

被引：78

作者：

Emmer, Brian T. ^{[1
,2
]}

Hesketh, Geoffrey G. ^{[3
]}

Kotnik, Emilee ^{[2
]}

Tang, Vi T. ^{[2
]}

Lascuna, Paul J. ^{[2
]}

Xiang, Jie ^{[2
]}

Gingras, Anne-Claude ^{[3
,4
]}

Chen, Xiao-Wei ^{[2
,5
]}

Ginsburg, David ^{[1
,2
,6
,7
,8
]}

机构：

[1] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA

[3] Sinai Hlth Syst, Lunenfeld Tanenbaum Res Inst, Ctr Syst Biol, Toronto, ON, Canada

[4] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada

[5] Peking Univ, Inst Mol Med, Ctr Life Sci, State Key Lab Membrane Biol, Beijing, Peoples R China

[6] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA

[7] Univ Michigan, Dept Pediat & Communicable Dis, Ann Arbor, MI 48109 USA

[8] Univ Michigan, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA

来源：

ELIFE | 2018年 / 7卷

关键词：

TRANSPORT RECEPTOR; GENE ONTOLOGY; PROTEINS; GENOME; RISK; ARCHITECTURE; DEGRADATION; SORTILIN; COMPLEX; EXPORT;

D O I：

10.7554/eLife.38839

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：18

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