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Vol. 10, Issue 12, 4059-4073, December 1999
*Department of Molecular Genetics, University and Biocenter Vienna,
Vienna, Austria; and §Department of Cell Biology, New York
University School of Medicine, New York, New York
We are studying endoplasmic reticulum-associated degradation
(ERAD) with the use of a truncated variant of the type I ER
transmembrane glycoprotein ribophorin I (RI). The mutant protein,
RI332, containing only the N-terminal 332 amino acids of
the luminal domain of RI, has been shown to interact with calnexin and
to be a substrate for the ubiquitin-proteasome pathway. When
RI332 was expressed in HeLa cells, it was degraded with
biphasic kinetics; an initial, slow phase of ~45 min was followed by
a second phase of threefold accelerated degradation. On the other hand,
the kinetics of degradation of a form of RI332 in which the
single used N-glycosylation consensus site had been removed
(RI332-Thr) was monophasic and rapid, implying a role of
the N-linked glycan in the first proteolytic phase. RI332
degradation was enhanced when the binding of glycoproteins to calnexin
was prevented. Moreover, the truncated glycoprotein interacted with
calnexin preferentially during the first proteolytic phase, which
strongly suggests that binding of RI332 to the lectin-like protein may result in the slow, initial phase of degradation. Additionally, mannose trimming appears to be required for efficient proteolysis of RI332. After treatment of cells with the
inhibitor of N-glycosylation, tunicamycin, destruction of the truncated RI variants was severely inhibited; likewise, in cells preincubated with the calcium ionophore A23187, both RI332 and
RI332-Thr were stabilized, despite the presence or absence
of the N-linked glycan. On the other hand, both drugs are known to
trigger the unfolded protein response (UPR), resulting in the induction
of BiP and other ER-resident proteins. Indeed, only in drug-treated
cells could an interaction between BiP and RI332 and
RI332-Thr be detected. Induction of BiP was also evident
after overexpression of murine Ire1, an ER transmembrane kinase known
to play a central role in the UPR pathway; at the same time,
stabilization of RI332 was observed. Together, these
results suggest that binding of the substrate proteins to UPR-induced
chaperones affects their half lives.
Dipartimento Medicina
Sperimentale e Diagnostica, Sezione di Patologia Generale,
Universitá di Ferrara, Ferrara, Italy;
Spiegelmayr Kommunikation, Schleissheim, Austria.
Corresponding author. E-mail address:
ivessa{at}mol.univie.ac.at.
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