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Elife. 2013 Apr 9;2:e00444. doi: 10.7554/eLife.00444.

SEC24A deficiency lowers plasma cholesterol through reduced PCSK9 secretion.

Author information

1
Life Sciences Institute , University of Michigan , Ann Arbor , United States.

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

PMID:
23580231
PMCID:
PMC3622177
DOI:
10.7554/eLife.00444
[Indexed for MEDLINE]
Free PMC Article

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