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Vol. 13, Issue 8, 2639-2650, August 2002
and
*Departments of Pathology, and Molecular and Cellular Biology,
Baylor College of Medicine, Houston, Texas 77030-3498; and
Protein folding and quality control in the early secretory pathway
function as posttranslational checkpoints in eukaryote gene expression.
Herein, an aberrant form of the hepatic secretory protein
Department of Biochemistry and Molecular Biology and
Complex Carbohydrate Research Center, University of
Georgia, Athens, Georgia 30602-7229
1-antitrypsin was stably expressed in a human embryonic kidney cell line to elucidate the mechanisms by which glycoprotein endoplasmic reticulum-associated degradation (GERAD) is administered in
cells from higher eukaryotes. After biosynthesis, genetic variant PI Z
underwent alternative phases of secretion and degradation, the latter
of which was mediated by the proteasome. Degradation required release
from calnexin- and asparagine-linked oligosaccharide modification by
endoplasmic reticulum mannosidase I, the latter of which occurred as PI
Z was bound to the molecular chaperone grp78/BiP. That a distinct GERAD
program operates in human embryonic kidney cells was supported by the
extent of PI Z secretion, apparent lack of polymerization, inability of
calnexin to participate in the degradation process, and sequestration
of the glycoprotein folding sensor UDP-glucose:glycoprotein
glucosyltransferase in the Golgi complex. Because
UDP-glucose:glycoprotein glucosyltransferase sustains calnexin binding,
its altered distribution is consistent with a GERAD program that
hinders the reentry of substrates into the calnexin cycle, allowing
grp78/BiP to partner with a lectin, other than calnexin, in the
recognition of a two-component GERAD signal to facilitate substrate
recruitment. How the processing of a mutant protein, rather than the
mutation itself, can contribute to disease pathogenesis, is discussed.
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