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Proc Natl Acad Sci U S A. 2015 Feb 3;112(5):1398-403. doi: 10.1073/pnas.1414593112. Epub 2015 Jan 20.

Endo-β-N-acetylglucosaminidase forms N-GlcNAc protein aggregates during ER-associated degradation in Ngly1-defective cells.

Author information

1
Glycometabolome Team, Systems Glycobiology Research Group, RIKEN-Max Planck Joint Research Center for Systems Chemical Biology, RIKEN Global Research Cluster, Wako, Saitama 351-0198, Japan; Graduate School of Science and Engineering, Saitama University, Saitama, Saitama 338-8570, Japan; and.
2
Glycometabolome Team, Systems Glycobiology Research Group, RIKEN-Max Planck Joint Research Center for Systems Chemical Biology, RIKEN Global Research Cluster, Wako, Saitama 351-0198, Japan;
3
Collaboration Promotion Unit, RIKEN Global Research Cluster, Wako, Saitama 351-0198, Japan.
4
Glycometabolome Team, Systems Glycobiology Research Group, RIKEN-Max Planck Joint Research Center for Systems Chemical Biology, RIKEN Global Research Cluster, Wako, Saitama 351-0198, Japan; Graduate School of Science and Engineering, Saitama University, Saitama, Saitama 338-8570, Japan; and tsuzuki_gm@riken.jp.

Abstract

The cytoplasmic peptide:N-glycanase (PNGase; Ngly1 in mice) is a deglycosylating enzyme involved in the endoplasmic reticulum (ER)-associated degradation (ERAD) process. The precise role of Ngly1 in the ERAD process, however, remains unclear in mammals. The findings reported herein, using mouse embryonic fibroblast (MEF) cells, that the ablation of Ngly1 causes dysregulation of the ERAD process. Interestingly, not only delayed degradation but also the deglycosylation of a misfolded glycoprotein was observed in Ngly1(-/-) MEF cells. The unconventional deglycosylation reaction was found to be catalyzed by the cytosolic endo-β-N-acetylglucosaminidase (ENGase), generating aggregation-prone N-GlcNAc proteins. The ERAD dysregulation in cells lacking Ngly1 was restored by the additional knockout of ENGase gene. Thus, our study underscores the functional importance of Ngly1 in the ERAD process and provides a potential mechanism underlying the phenotypic consequences of a newly emerging genetic disorder caused by mutation of the human NGLY1 gene.

KEYWORDS:

ENGase; ERAD; PNGase (Ngly1); glycoprotein; protein aggregates

PMID:
25605922
PMCID:
PMC4321286
DOI:
10.1073/pnas.1414593112
[Indexed for MEDLINE]
Free PMC Article

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