Loss of peptide: N -glycanase causes proteasome dysfunction mediated by a sugar-recognizing ubiquitin ligase
| Autor: | Arisa Murakami, Tadashi Suzuki, Noriyuki Matsuda, Kazuhiro Iwai, Reiko Fujinawa, Yukiko Yoshida, Keiji Tanaka, Ryuichi Tozawa, Makoto Asahina, Meari Yoshida, Junko Kawawaki |
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| Rok vydání: | 2021 |
| Předmět: |
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 |
| Zdroj: | Proceedings of the National Academy of Sciences. 118 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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