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Vol. 19, Issue 1, 216-225, January 2008

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Endoplasmic Reticulum (ER) Mannosidase I Is Compartmentalized and Required for N-Glycan Trimming to Man_5–6GlcNAc₂ in Glycoprotein ER-associated Degradation

Edward Avezov^*, Zehavit Frenkel^*, Marcelo Ehrlich^*, Annette Herscovics, and Gerardo Z. Lederkremer^*

*Department of Cell Research and Immunology, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel; and McGill Cancer Centre, McGill University, Montréal, Quebec, Canada H3G 1Y6

Submitted May 29, 2007; Revised September 25, 2007; Accepted November 1, 2007
Monitoring Editor: Reid Gilmorez

We had previously shown that endoplasmic reticulum (ER)-associated degradation (ERAD) of glycoproteins in mammalian cells involves trimming of three to four mannose residues from the N-linked oligosaccharide Man₉GlcNAc₂. A possible candidate for this activity, ER mannosidase I (ERManI), accelerates the degradation of ERAD substrates when overexpressed. Although in vitro, at low concentrations, ERManI removes only one specific mannose residue, at very high concentrations it can excise up to four 1,2-linked mannose residues. Using small interfering RNA knockdown of ERManI, we show that this enzyme is required for trimming to Man_5–6GlcNAc₂ and for ERAD in cells in vivo, leading to the accumulation of Man₉GlcNAc₂ and Glc₁Man₉GlcNAc₂ on a model substrate. Thus, trimming by ERManI to the smaller oligosaccharides would remove the glycoprotein from reglucosylation and calnexin binding cycles. ERManI is strikingly concentrated together with the ERAD substrate in the pericentriolar ER-derived quality control compartment (ERQC) that we had described previously. ERManI knockdown prevents substrate accumulation in the ERQC. We suggest that the ERQC provides a high local concentration of ERManI, and passage through this compartment would allow timing of ERAD, possibly through a cycling mechanism. When newly made glycoproteins cannot fold properly, transport through the ERQC leads to trimming of a critical number of mannose residues, triggering a signal for degradation.

Address correspondence to: Gerardo Z. Lederkremer (gerardo{at}post.tau.ac.il)

Abbreviations used: dMNJ, 1-deoxymannojirimycin; endo H, endo-β-N-acetylglucosaminidase H; ER, endoplasmic reticulum; ERAD, endoplasmic reticulum-associated degradation; ERManI, ER mannosidase I; ERQC, endoplasmic reticulum-derived quality control compartment; KIF, kifunensine; lac, lactacystin; MG-132, N-carbobenzoxyl-leucinyl-leucinyl-leucinal; UGGT, UDP-Glc:glycoprotein glucosyltransferase.

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