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PMID: 23580231 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

SEC24A deficiency lowers plasma cholesterol through reduced PCSK9 secretion.

eLife ·Vol. 2 ·2013-04-09 ·Pages e00444

Chen XW, Wang H, Bajaj K, Zhang P, Meng ZX, Ma D, Bai Y, Liu HH, Adams E, Baines A, Yu G, Sartor MA, Zhang B, Yi Z, Lin J, Young SG, Schekman R, Ginsburg D

Abstract

The secretory pathway of eukaryotic cells packages cargo proteins into COPII-coated vesicles for transport from the endoplasmic reticulum (ER) to the Golgi. We now report that complete genetic deficiency for the COPII component SEC24A is compatible with normal survival and development in the mouse, despite the fundamental role of SEC24 in COPII vesicle formation and cargo recruitment. However, these animals exhibit markedly reduced plasma cholesterol, with mutations in Apoe and Ldlr epistatic to Sec24a, suggesting a receptor-mediated lipoprotein clearance mechanism. Consistent with these data, hepatic LDLR levels are up-regulated in SEC24A-deficient cells as a consequence of specific dependence of PCSK9, a negative regulator of LDLR, on SEC24A for efficient exit from the ER. Our findings also identify partial overlap in cargo selectivity between SEC24A and SEC24B, suggesting a previously unappreciated heterogeneity in the recruitment of secretory proteins to the COPII vesicles that extends to soluble as well as trans-membrane cargoes. DOI:http://dx.doi.org/10.7554/eLife.00444.001.

Keywords
COP II Cholesterol metabolism Mouse Secretory pathway
MeSH Terms
Animals Apolipoproteins E/genetics,metabolism COP-Coated Vesicles/enzymology,metabolism Cell Line, Tumor Cholesterol/blood Down-Regulation Dyslipidemias/blood,enzymology,genetics Endoplasmic Reticulum/enzymology,metabolism Epistasis, Genetic Genotype HEK293 Cells Humans Liver/enzymology,metabolism Mice, 129 Strain Mice, Inbred C57BL Mice, Knockout Mutation Phenotype Proprotein Convertase 9 Proprotein Convertases/blood,metabolism Protein Transport Receptors, LDL/genetics,metabolism Serine Endopeptidases/blood,metabolism Transfection Vesicular Transport Proteins/deficiency,genetics,metabolism
Chemicals
Apolipoproteins E Receptors, LDL SEC24A protein, mouse SEC24b protein, mouse Vesicular Transport Proteins Cholesterol Pcsk9 protein, mouse Proprotein Convertase 9 Proprotein Convertases Serine Endopeptidases
Authors & Affiliations
18 authors, click to expand affiliations / ORCID
Chen Xiao-Wei
Life Sciences Institute , University of Michigan , Ann Arbor , United States.
Wang He
Bajaj Kanika
Zhang Pengcheng
Meng Zhuo-Xian
Ma Danjun
Bai Yongsheng
Liu Hui-Hui
Adams Elizabeth
Baines Andrea
Yu Genggeng
Sartor Maureen A
Zhang Bin
Yi Zhengping
Lin Jiandie
Young Stephen G
Schekman Randy
Ginsburg David
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Article Info
Journal
eLife
Abbr.
Elife
ISSN
2050-084X
DOI
10.7554/eLife.00444
Published
2013-04-09
Epub
2013-00-09
Pages
e00444
Language
English
Region
England
NLM ID
101579614
PMCID
PMC3622177
Subset
IM
Grants
NHLBI NIH HHS · P01 HL057346 · United States
NHLBI NIH HHS · R01 HL087228 · United States
NHLBI NIH HHS · R01 HL094505 · United States
NHLBI NIH HHS · P01 HL090553 · United States
NHLBI NIH HHS · R01 HL039693 · United States
NHLBI NIH HHS · P01HL057346 · United States
NIDDK NIH HHS · P30 DK020572 · United States
NHLBI NIH HHS · R01HL039693 · United States
NIGMS NIH HHS · T32 GM007315 · United States
Corrections
CommentIn
PMID: 23580362
External Links
PubMed source DOI: 10.7554/eLife.00444 PMC Full Text View journal details
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