SEC24A deficiency lowers plasma cholesterol through reduced PCSK9 secretion
2013
The
secretory pathwayof 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
COPIIcomponent SEC24A is compatible with normal survival and development in the mouse, despite the fundamental role of SEC24 in
COPIIvesicle 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 proteinsto the
COPIIvesicles that extends to soluble as well as trans-membrane cargoes. DOI: http://dx.doi.org/10.7554/eLife.00444.001
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