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Journal of Cell Science, Vol 112, Issue 19 3309-3318, Copyright © 1999 by Company of Biologists
JOURNAL ARTICLES |
M Ayalon-Soffer, M Shenkman and GZ Lederkremer
Department of Cell Research and Immunology, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel, 69978.
To gain insight into how sugar chain processing events modulate endoplasmic reticulum (ER)/proteasomal degradation we looked at human asialoglycoprotein receptor polypeptides H2a and H2b, variants which differ only by an extra pentapeptide (EGHRG) present in H2a. Membrane-bound H2a is a precursor of a soluble secreted form while H2b reaches the plasma membrane. Uncleaved precursor H2a molecules are completely retained in the ER and degraded as well as a portion of H2b. Inhibition of N-linked sugar chain mannose trimming stabilized both variants. In contrast, inhibition of glucose trimming with castanospermine greatly enhanced the degradation rate of H2a but not that of H2b. We studied a possible involvement of the ER chaperone calnexin, as inhibitors of glucose trimming are known to prevent calnexin binding. Incubation of cells with low concentrations of castanospermine (30 microg/ml) did not interfere with calnexin binding to H2a while causing the same accelerated degradation as high concentrations (>100 microg/ml) which did inhibit the association. Castanospermine treatment after calnexin binding blocked the dissociation of the chaperone but still caused accelerated degradation. The increased degradation could be blocked by a specific proteasome inhibitor, ZL(3)VS. Our results suggest that extensive mannose trimming or retention of glucose residues due to lack of glucose trimming are signals for ER/proteasomal degradation independent of interaction with calnexin.
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