Endocytosis and degradation of α1-Antitrypsin-protease complexes is mediated by the serpin-enzyme complex (SEC) receptor

D. H. Perlmutter, G. Joslin, P. Nelson, C. Schasteen, S. P. Adams, R. J. Fallon

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α1-Antitrypsin (α1-AT) is similar to other members of the serine protease inhibitor (serpin) supergene family in that it undergoes structural rearrangement during the formation of a covalently stabilized inhibitory complex with its cognate enzyme, neutrophil elastase. We have recently demonstrated an abundant, high-affinity cell surface receptor on human hepatoma cells and human mononuclear phagocytes which recognizes a conformation-specific domain of the α1-AT-elastase complex as well as of other serpin-enzyme complexes (Perlmutter, D. H., Glover, G. I., Rivetna, M., Schasteen, C. S., and Fallon, R.J. (1990) Proc. Natl. Acad. Sci. U. S. A. 87, 3753-3757). Binding to this serpin-enzyme complex (SEC) receptor activates a signal transduction pathway for increased expression of the α1-AT gene and may be responsible for clearance of serpin-enzyme complexes. In this study, we show that there is time-dependent and saturable internalization of α1-AT-elastase and α1-AT-trypsin complexes in human hepatoma HepG2 cells. Internalization is mediated by the SEC receptor as defined by inhibition by synthetic peptides corresponding to residues 359-374 of α1-AT. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of intracellular radioactivity demonstrated that intact 75- and 66-kDa α1-AT-trypsin complexes were internalized. Kinetic analysis of internalization at 37 °C showed that a single cohort of 125I-α1-AT-trypsin complexes, prebound to cells at 4 °C, disappeared from the cell surface and accumulated intracellularly within 5-15 min at 37 °C. The intracellular concentration of radiolabeled complexes then decreased rapidly coincident with appearance of acid-soluble degradation products in the extracellular culture fluid. Intracellular degradation was inhibited by internalization at 18 °C or by internalization at 37 °C in the presence of weak bases ammonium chloride, primaquine, and chloroquine, indicating that degradation is lysosomal. These results indicate that in addition to its role in signal transduction the SEC receptor participates in internalization and delivery of α1-AT-protease complexes to lysosome for degradation.

Original languageEnglish
Pages (from-to)16713-16716
Number of pages4
JournalJournal of Biological Chemistry
Issue number28
StatePublished - 1990

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