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Identification of ERGIC-53 as an Intracellular Transport Receptor of α₁-Antitrypsin

Beat Nyfeler, Veronika Reiterer, Markus W. Wendeler, Eduard Stefan, Bin Zhang, Stephen W. Michnick and Hans-Peter Hauri
The Journal of Cell Biology
Vol. 180, No. 4 (Feb. 25, 2008), pp. 705-712
Stable URL: http://www.jstor.org/stable/20475809
Page Count: 8
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Identification of ERGIC-53 as an Intracellular Transport Receptor of α₁-Antitrypsin
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Abstract

Secretory proteins are exported from the endoplasmic reticulum (ER) by bulk flow and/or receptor-mediated transport. Our understanding of this process is limited because of the low number of identified transport receptors and cognate cargo proteins. In mammalian cells, the lectin ER Golgi intermediate compartment 53-kD protein (ERGIC-53) represents the best characterized cargo receptor. It assists ER export of a subset of glycoproteins including coagulation factors V and VIII and cathepsin C and Z. Here, we report a novel screening strategy to identify protein interactions in the lumen of the secretory pathway using a yellow fluorescent protein-based protein fragment complementation assay. By screening a human liver complementary DNA library, we identify α1-antitrypsin (α1-AT) as previously unrecognized cargo of ERGIC-53 and show that cargo capture is carbohydrate- and conformation-dependent. ERGIC-53 knockdown and knockout cells display a specific secretion defect of α1-AT that is corrected by reintroducing ERGIC-53. The results reveal ERGIC-53 to be an intracellular transport receptor of α1-AT and provide direct evidence for active receptor-mediated ER export of a soluble secretory protein in higher eukaryotes.

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