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MBC in Press, published online ahead of print November 14, 2007
Mol. Biol. Cell 10.1091/mbc.E07-05-0505

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Submitted on May 29, 2007
Revised on September 25, 2007
Accepted on November 1, 2007

ER Mannosidase I Is Compartmentalized and Required for N-Glycan Trimming to Man5–6GlcNAc2 in Glycoprotein ER-associated Degradation

Edward Avezov,* Zehavit Frenkel,* Marcelo Ehrlich,* Annette Herscovics,{dagger} and Gerardo Z. Lederkremer*

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

Monitoring Editor: Reid Gilmorez

We had previously shown that ER-associated degradation (ERAD) of glycoproteins in mammalian cells involves trimming of 3–4 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 4 {alpha}1,2-linked mannose residues. Using siRNA knock-down of ERManI, we show that this enzyme is required for trimming to Man5–6GlcNAc2 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 appears strikingly concentrated together with the ERAD substrate in the pericentriolar ER-derived quality control compartment (ERQC) that we had described previously. ERManI knock-down 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)




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