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.
Highlights
One-third of the vertebrate genome is predicted to encode proteins that are sorted into the secretory pathway en route to intracellular organelles, the cell surface, or the extracellular space (Palade, 1975; Bonifacino and Glick, 2004)
The finding that complete deficiency of the complex II (COPII) subunit SEC24A is compatible with normal survival and development in the mouse is surprising, in light of its ubiquitous expression and presumed fundamental function in the secretory pathway
Apoe and Ldlr are epistatic to Sec24a, suggesting that SEC24A primarily affects receptor-mediated cholesterol clearance of cholesterol-rich lipoproteins
Summary
One-third of the vertebrate genome is predicted to encode proteins that are sorted into the secretory pathway en route to intracellular organelles, the cell surface, or the extracellular space (Palade, 1975; Bonifacino and Glick, 2004). Following synthesis in the endoplasmic reticulum, trans-membrane and soluble proteins co-translationally inserted into the ER are packaged into transport vesicles coated with COPII (coat protein complex II) for export from the ER and delivery to the Golgi for further processing (Lee et al, 2004). Biochemistry | Cell biology eLife digest The endoplasmic reticulum (ER) is a structure that performs a variety of functions within eukaryotic cells. It can be divided into two regions: the surface of the rough ER is coated with ribosomes that manufacture various proteins, while the smooth ER is involved in activities such as lipid synthesis and carbohydrate metabolism. Proteins synthesized by the ribosomes attached to the rough ER are generally transferred to another structure within the cell, the Golgi apparatus, where they undergo further processing and packaging before being secreted or transported to another location within the cell
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