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J. Biol. Chem., Vol. 278, Issue 36, 34119-34124, September 5, 2003

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Endoplasmic Reticulum-associated Degradation of Mammalian Glycoproteins Involves Sugar Chain Trimming to Man_6–5GlcNAc₂^*

Zehavit Frenkel , Walter Gregory , Stuart Kornfeld  and Gerardo Z. Lederkremer  ¶

From the Department of Cell Research and Immunology, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel and Division of Hematology, Washington University School of Medicine, St. Louis, Missouri 63110

Endoplasmic reticulum-associated degradation of misfolded or misprocessed glycoproteins in mammalian cells is prevented by inhibitors of class I -mannosidases implicating mannose trimming from the precursor oligosaccharide Glc₃Man₉GlcNAc₂ as an essential step in this pathway. However, the extent of mannose removal has not been determined. We show here that glycoproteins subject to endoplasmic reticulum-associated degradation undergo reglucosylation, deglucosylation, and mannose trimming to yield Man₆GlcNAc₂ and Man₅GlcNAc₂. These structures lack the mannose residue that is the acceptor of glucose transferred by UDP-Glc:glycoprotein glucosyltransferase. This could serve as a mechanism for removal of the glycoproteins from folding attempts catalyzed by cycles of reglucosylation and calnexin/calreticulin binding and result in targeting of these molecules for proteasomal degradation.

Received for publication, June 5, 2003 , and in revised form, June 19, 2003.

^* This work was supported by a grant from the United States-Israel Binational Science Foundation and a grant from the Israel Science Foundation (to G. Z. L.), founded by the Israeli Academy of Sciences.

^¶ To whom correspondence should be addressed. Tel.: 972-3-640-9239; Fax: 972-3-642-2046; E-mail: gerardo{at}post.tau.ac.il.

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