title: SEC24A deficiency lowers plasma cholesterol through reduced PCSK9 secretion.
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.
authors.affiliation: Life Sciences Institute , University of Michigan , Ann Arbor , United States.
authors.forename: Xiao-Wei
authors.initials: XW
authors.lastname: Chen
authors.forename: He
authors.initials: H
authors.lastname: Wang
authors.forename: Kanika
authors.initials: K
authors.lastname: Bajaj
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Zhang
authors.forename: Zhuo-Xian
authors.initials: ZX
authors.lastname: Meng
authors.forename: Danjun
authors.initials: D
authors.lastname: Ma
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Bai
authors.forename: Hui-Hui
authors.initials: HH
authors.lastname: Liu
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Adams
authors.forename: Andrea
authors.initials: A
authors.lastname: Baines
authors.forename: Genggeng
authors.initials: G
authors.lastname: Yu
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Sartor
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Yi
authors.forename: Jiandie
authors.initials: J
authors.lastname: Lin
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Young
authors.forename: Randy
authors.initials: R
authors.lastname: Schekman
authors.forename: David
authors.initials: D
authors.lastname: Ginsburg
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D022181:COP-Coated Vesicles / Q000201:enzymology* / Q000378:metabolism; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000097:blood*; D015536:Down-Regulation; D050171:Dyslipidemias / Q000097:blood / Q000201:enzymology* / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000201:enzymology* / Q000378:metabolism; D004843:Epistasis, Genetic; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D010641:Phenotype; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000097:blood* / Q000378:metabolism; D021381:Protein Transport; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000097:blood* / Q000378:metabolism; D014162:Transfection; D033921:Vesicular Transport Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D011973:Receptors, LDL; C000598120:SEC24A protein, mouse; C548501:SEC24b protein, mouse; D033921:Vesicular Transport Proteins; D002784:Cholesterol; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: COP II; Cholesterol metabolism; Mouse; Secretory pathway