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The cargo receptor SURF4 promotes the efficient cellular secretion of PCSK9

Emmer, Brian T, Hesketh, Geoffrey G, Kotnik, Emilee, Tang, Vi T, Lascuna, Paul J, Xiang, Jie, Gingras, Anne-Claude, Chen, Xiao-Wei, Ginsburg, David·2018·eLife
DOI 10.7554/elife.38839PMC PMC6156083

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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.

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  • The authors previously performed a genome-wide CRISPR screen for the molecular determinants of PCSK9 secretion, leading to identification of SURF4 as a cargo receptor that recruits PCSK9 into the secretory pathway.

    “We previously performed a genome-wide CRISPR screen for the molecular determinants of PCSK9 secretion, leading to our identification of SURF4 as a cargo receptor that recruits PCSK9 into the secretory pathway[14].”

    From Genome-scale CRISPR screening for modifiers of cellular LDL uptake (2021) · cites this paper as [14]

  • Library diversity was assessed with a Illumina MiSeq run of gRNA amplicons prepared as previously described.

    “Library diversity was assessed with a Illumina MiSeq run of gRNA amplicons prepared as previously described[14].”

    From Genome-scale CRISPR screening for modifiers of cellular LDL uptake (2021) · cites this paper as [14]

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Metadata

Authors
Emmer, B. T., Hesketh, G. G., Kotnik, E., Tang, V. T., Lascuna, P. J., Xiang, J., Gingras, A.-C., Chen, X.-W., & Ginsburg, D.
Affiliations
  • Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
  • Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada
  • Life Sciences Institute, University of Michigan, Ann Arbor, Michigan
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2018-09-25
Volume
7
ISSN
2050-084X
DOI
10.7554/elife.38839
PMC
PMC6156083
Cited by
96
References
6
Language
en
Licence
Funders
National Heart, Lung, and Blood Institute (R35-HL135793T, T32-HL007853)

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