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Loss of peptide
- Source :
- Proc Natl Acad Sci U S A
- Publication Year :
- 2021
-
Abstract
- Mutations in the human peptide:N-glycanase gene (NGLY1), which encodes a cytosolic de–N-glycosylating enzyme, cause a congenital autosomal recessive disorder. In rodents, the loss of Ngly1 results in severe developmental delay or lethality, but the underlying mechanism remains unknown. In this study, we found that deletion of Fbxo6 (also known as Fbs2), which encodes a ubiquitin ligase subunit that recognizes glycoproteins, rescued the lethality-related defects in Ngly1-KO mice. In NGLY1-KO cells, FBS2 overexpression resulted in the substantial inhibition of proteasome activity, causing cytotoxicity. Nuclear factor, erythroid 2–like 1 (NFE2L1, also known as NRF1), an endoplasmic reticulum–associated transcriptional factor involved in expression of proteasome subunits, was also abnormally ubiquitinated by SCF(FBS2) in NGLY1-KO cells, resulting in its retention in the cytosol. However, the cytotoxicity caused by FBS2 was restored by the overexpression of “glycan-less” NRF1 mutants, regardless of their transcriptional activity, or by the deletion of NRF1 in NGLY1-KO cells. We conclude that the proteasome dysfunction caused by the accumulation of N-glycoproteins, primarily NRF1, ubiquitinated by SCF(FBS2) accounts for the pathogenesis resulting from NGLY1 deficiency.
- Subjects :
- Cell Nucleus
Mice, Knockout
Proteasome Endopeptidase Complex
SKP Cullin F-Box Protein Ligases
Behavior, Animal
Cell Death
Nuclear Respiratory Factor 1
Ubiquitination
Motor Activity
Biological Sciences
HCT116 Cells
Models, Biological
Mice, Inbred C57BL
Protein Transport
Cytosol
Polysaccharides
Mutation
Animals
Humans
Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase
Sugars
Cell Proliferation
HeLa Cells
Subjects
Details
- ISSN :
- 10916490
- Volume :
- 118
- Issue :
- 27
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Accession number :
- edsair.pmid..........f99856f479a40fe48f3db6cbf1379944