Mannosidase IA is in Quality Control Vesicles and Participates in Glycoprotein Targeting to ERAD.
Endoplasmic reticulum-associated degradation (ERAD) of a misfolded glycoprotein in mammalian cells requires the removal of 3-4 alpha 1,2 linked mannose residues from its N-glycans. The trimming and recognition processes are ascribed to ER Mannosidase I, the ER-degradation enhancing mannosidase-like proteins (EDEMs), and the lectins OS-9 and XTP3-B, all residing in the ER, the ER-derived quality control compartment (ERQC), or quality control vesicles (QCVs). Folded glycoproteins with untrimmed glycans are transported from the ER to the Golgi complex, where they are substrates of other alpha 1,2 mannosidases, IA, IB, and IC. The apparent redundancy of these enzymes has been puzzling for many years. We have now determined that, surprisingly, mannosidase IA is not located in the Golgi but resides in QCVs. We had recently described this type of vesicles, which carry ER α1,2 mannosidase I (ERManI). We show that the overexpression of alpha class I α1,2 mannosidase IA (ManIA) significantly enhances the degradation of ERAD substrates and its knockdown stabilizes it. Our results indicate that ManIA trims mannose residues from Man9GlcNAc2 down to Man5GlcNAc2, acting in parallel with ERManI and the EDEMs, and targeting misfolded glycoproteins to ERAD.
Department of Cell Research and Immunology, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
Navit
N
Ogen-Shtern
Department of Cell Research and Immunology, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
Edward
E
Avezov
Department of Cell Research and Immunology, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
Marina
M
Shenkman
Department of Cell Research and Immunology, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
Ron
R
Benyair
Department of Cell Research and Immunology, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: gerardo@post.tau.ac.il.
Gerardo Z
GZ
Lederkremer
D000818:Animals; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D060746:Endoplasmic Reticulum-Associated Degradation / Q000502:physiology*; D006023:Glycoproteins / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D037102:Lectins / Q000378:metabolism; D008358:Mannose / Q000378:metabolism; D008361:Mannosidases / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D011134:Polysaccharides / Q000378:metabolism; D017510:Protein Folding
D006023:Glycoproteins; D037102:Lectins; D008565:Membrane Proteins; D011134:Polysaccharides; D008361:Mannosidases; C046090:mannosyl-oligosaccharide 1,2-alpha-mannosidase; D008358:Mannose
ER mannosidase; ER quality control; Golgi; glycosylation; mannose trimming