Golgi localization of ERManI defines spatial separation of the mammalian glycoprotein quality control system

The Golgi complex has been implicated as a possible component of endoplasmic reticulum (ER) glycoprotein quality control, although the elucidation of its exact role is lacking. ERManI, a putative ER resident mannosidase, plays a rate-limiting role in generating a signal that targets misfolded N-link...

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Bibliographic Details
Published in:Molecular biology of the cell 2011-08, Vol.22 (16), p.2810-2822
Main Authors: Pan, Shujuan, Wang, Shufang, Utama, Budi, Huang, Lu, Blok, Neil, Estes, Mary K, Moremen, Kelley W, Sifers, Richard N
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Antibodies, Monoclonal, Murine-Derived - chemistry
Binding Sites
Cell Line
Cricetinae
Cricetulus
Endoplasmic Reticulum - metabolism
Glycoproteins - metabolism
Glycosylation
Golgi Apparatus - metabolism
Humans
Mannosidases - chemistry
Mannosidases - metabolism
Mice
Mice, Inbred BALB C
Molecular Sequence Data
Peptide Fragments - chemistry
Peptide Fragments - metabolism
Protein Folding
Protein Structure, Tertiary
Protein Transport
Proteolysis
Solubility
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Summary:The Golgi complex has been implicated as a possible component of endoplasmic reticulum (ER) glycoprotein quality control, although the elucidation of its exact role is lacking. ERManI, a putative ER resident mannosidase, plays a rate-limiting role in generating a signal that targets misfolded N-linked glycoproteins for ER-associated degradation (ERAD). Herein we demonstrate that the endogenous human homologue predominantly resides in the Golgi complex, where it is subjected to O-glycosylation. To distinguish the intracellular site where the glycoprotein ERAD signal is generated, a COPI-binding motif was appended to the N terminus of the recombinant protein to facilitate its retrograde translocation back to the ER. Partial redistribution of the modified ERManI was observed along with an accelerated rate at which N-linked glycans of misfolded α1-antitrypsin variant NHK were trimmed. Despite these observations, the rate of NHK degradation was not accelerated, implicating the Golgi complex as the site for glycoprotein ERAD substrate tagging. Taken together, these data provide a potential mechanistic explanation for the spatial separation by which glycoprotein quality control components operate in mammalian cells.
ISSN:1059-1524
1939-4586
DOI:10.1091/mbc.e11-02-0118