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Loss of peptide: N -glycanase causes proteasome dysfunction mediated by a sugar-recognizing ubiquitin ligase
- Source :
- Proceedings of the National Academy of Sciences. 118
- Publication Year :
- 2021
- Publisher :
- Proceedings of the National Academy of Sciences, 2021.
-
Abstract
- Significance Cytosolic peptide: N -glycanase (NGLY1) is a widely conserved enzyme involved in de– N -glycosylation of N -glycosylated proteins. Mutations in the human NGLY1 gene cause global developmental delay and multisystemic symptoms, but the molecular mechanism underlying pathogenesis remains poorly understood. FBXO6/FBS2, a subunit of the SCF (SKP1–CUL1–F-box protein) ubiquitin ligase complex, recognizes N -glycans of cytosolic glycoproteins in the endoplasmic reticulum–associated degradation (ERAD) pathway. This paper reports that high levels of ERAD glycoprotein substrates abnormally ubiquitinated by SCF FBS2 in the absence of NGLY1 impair the proteasome, contributing to the pathogenesis of NGLY1 deficiency. Importantly, knockout of Fbxo6/Fbs2 rescued the lethality of NGLY1 deficiency in mice, suggesting a strategy for developing therapeutics for this intractable disease.
- Subjects :
- 0303 health sciences
Multidisciplinary
biology
Chemistry
Endoplasmic reticulum
Endoplasmic-reticulum-associated protein degradation
NFE2L1
Ubiquitin ligase
Cell biology
03 medical and health sciences
0302 clinical medicine
Ubiquitin
Proteasome
biology.protein
NRF1
NGLY1
030217 neurology & neurosurgery
030304 developmental biology
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 118
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi...........adf03503537a194f00f5f1f2207ff077