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Published online February 18, 2008
doi:10.1083/jcb.200709100
The Journal of Cell Biology, Vol. 180, No. 4, 705-712
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Nyfeler et al.
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Identification of ERGIC-53 as an intracellular transport receptor of {alpha}1-antitrypsin



Beat Nyfeler1, Veronika Reiterer1, Markus W. Wendeler1, Eduard Stefan2, Bin Zhang3, Stephen W. Michnick2, and Hans-Peter Hauri1

1 Biozentrum, University of Basel, CH-4056 Basel, Switzerland
2 Département de Biochimie, Université de Montréal, Montréal, Québec, Canada H3C 3J7
3 Genomic Medicine Institute, Lerner Research Institute of Cleveland Clinic, Cleveland, OH 44195

Correspondence to H.-P. Hauri: Hans-Peter.Hauri{at}unibas.ch

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 {alpha}1-antitrypsin ({alpha}1-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 {alpha}1-AT that is corrected by reintroducing ERGIC-53. The results reveal ERGIC-53 to be an intracellular transport receptor of {alpha}1-AT and provide direct evidence for active receptor-mediated ER export of a soluble secretory protein in higher eukaryotes.

Abbreviations used in this paper: {alpha}1-AT, {alpha}1-antitrypsin; COPII, coat protein II; ERGIC, ER Golgi intermediate compartment; MCFD2, multiple coagulation factor deficiency protein 2; MEF, mouse embryonic fibroblast; PCA, protein fragment complementation assay.


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