Loss of N-Glycanase 1 Alters Transcriptional and Translational Regulation in K562 Cell Lines.
NFE2L1
NGLY1deficiency
NRF1
autophagy
deglycosylation
Journal
G3 (Bethesda, Md.)
ISSN: 2160-1836
Titre abrégé: G3 (Bethesda)
Pays: England
ID NLM: 101566598
Informations de publication
Date de publication:
04 05 2020
04 05 2020
Historique:
pubmed:
9
4
2020
medline:
22
6
2021
entrez:
9
4
2020
Statut:
epublish
Résumé
N-Glycanase 1 (NGLY1) deficiency is an ultra-rare, complex and devastating neuromuscular disease. Patients display multi-organ symptoms including developmental delays, movement disorders, seizures, constipation and lack of tear production. NGLY1 is a deglycosylating protein involved in the degradation of misfolded proteins retrotranslocated from the endoplasmic reticulum (ER). NGLY1-deficient cells have been reported to exhibit decreased deglycosylation activity and an increased sensitivity to proteasome inhibitors. We show that the loss of NGLY1 causes substantial changes in the RNA and protein landscape of K562 cells and results in downregulation of proteasomal subunits, consistent with its processing of the transcription factor NFE2L1. We employed the CMap database to predict compounds that can modulate NGLY1 activity. Utilizing our robust K562 screening system, we demonstrate that the compound NVP-BEZ235 (Dactosilib) promotes degradation of NGLY1-dependent substrates, concurrent with increased autophagic flux, suggesting that stimulating autophagy may assist in clearing aberrant substrates during NGLY1 deficiency.
Identifiants
pubmed: 32265286
pii: g3.119.401031
doi: 10.1534/g3.119.401031
pmc: PMC7202010
doi:
Substances chimiques
Proteasome Endopeptidase Complex
EC 3.4.25.1
NGLY1 protein, human
EC 3.5.1.52
Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase
EC 3.5.1.52
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1585-1597Informations de copyright
Copyright © 2020 Mueller et al.
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