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J. Biol. Chem., Vol. 265, Issue 28, 16713-16716, 10, 1990
DH Perlmutter, G Joslin, P Nelson, C Schasteen, SP Adams and RJ Fallon
Alpha 1-Antitrypsin (alpha 1-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 alpha 1-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 alpha 1-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 alpha 1-AT-elastase and
alpha 1-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 alpha 1-AT. Sodium dodecyl
sulfate- polyacrylamide gel electrophoresis analysis of intracellular
radioactivity demonstrated that intact 75- and 66-kDa alpha 1-AT- trypsin
complexes were internalized. Kinetic analysis of internalization at 37
degrees C showed that a single cohort of 125I- alpha 1-AT-trypsin
complexes, prebound to cells at 4 degrees C, disappeared from the cell
surface and accumulated intracellularly within 5-15 min at 37 degrees 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 degrees C or by internalization at 37 degrees 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 alpha 1-AT- protease complexes to
lysosome for degradation.
Endocytosis and degradation of alpha 1-antitrypsin-protease complexes is mediated by the serpin-enzyme complex (SEC) receptor
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110.
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