NGLY1: A fascinating, multifunctional molecule

Suzuki, Tadashi; Fujihira, Haruhiko

doi:10.1016/j.bbagen.2023.130379

Cited by 7 publications

(1 citation statement)

References 67 publications

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“…N-linked glycosylation is a posttranslational modification of Asparagine residues of proteins that are in the ER lumen ( Suzuki and Fujihira, 2024 ; Suzuki et al, 2016 ; Suzuki and Yoshida, 2022 ). NGlycanase-1 (NGLY1) is an evolutionarily conserved enzyme that removes N-linked glycosylation from cytosolic proteins (de-glycosylation).…”

Section: Resultsmentioning

confidence: 99%

Transcription factor Nrf1 regulates proteotoxic stress-induced autophagy

Ward,

Vangala,

Kamber Kaya

et al. 2024

Journal of Cell Biology

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Cells exposed to proteotoxic stress invoke adaptive responses aimed at restoring proteostasis. Our previous studies have established a firm role for the transcription factor Nuclear factor-erythroid derived-2-related factor-1 (Nrf1) in responding to proteotoxic stress elicited by inhibition of cellular proteasome. Following proteasome inhibition, Nrf1 mediates new proteasome synthesis, thus enabling the cells to mitigate the proteotoxic stress. Here, we report that under similar circumstances, multiple components of the autophagy–lysosomal pathway (ALP) were transcriptionally upregulated in an Nrf1-dependent fashion, thus providing the cells with an additional route to cope with proteasome insufficiency. In response to proteasome inhibitors, Nrf1-deficient cells displayed profound defects in invoking autophagy and clearance of aggresomes. This phenomenon was also recapitulated in NGLY1 knockout cells, where Nrf1 is known to be non-functional. Conversely, overexpression of Nrf1 induced ALP genes and endowed the cells with an increased capacity to clear aggresomes. Overall, our results significantly expand the role of Nrf1 in shaping the cellular response to proteotoxic stress.

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Section: Resultsmentioning

confidence: 99%

Transcription factor Nrf1 regulates proteotoxic stress-induced autophagy

Ward,

Vangala,

Kamber Kaya

et al. 2024

Journal of Cell Biology

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Structural basis of sugar recognition by SCF^FBS2 ubiquitin ligase involved in NGLY1 deficiency

Satoh,

Yagi‐Utsumi,

Ishii

et al. 2024

FEBS Letters

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The cytosolic peptide:N‐glycanase (PNGase) is involved in the quality control of N‐glycoproteins via the endoplasmic reticulum‐associated degradation (ERAD) pathway. Mutations in the gene encoding cytosolic PNGase (NGLY1 in humans) cause NGLY1 deficiency. Recent findings indicate that the F‐box protein FBS2 of the SCFFBS2 ubiquitin ligase complex can be a promising drug target for NGLY1 deficiency. Here, we determined the crystal structure of bovine FBS2 complexed with the adaptor protein SKP1 and a sugar ligand, Man3GlcNAc2, which corresponds to the core pentasaccharide of N‐glycan. Our crystallographic data together with NMR data revealed the structural basis of disparate sugar‐binding specificities in homologous FBS proteins and identified a potential druggable pocket for in silico docking studies. Our results provide a potential basis for the development of selective inhibitors against FBS2 in NGLY1 deficiency.

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ELISA-based highly sensitive assay system for the detection of endogenous NGLY1 activity

Fujihira,

Sato,

Nishiuchi

et al. 2024

Biochemical and Biophysical Research Communications

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NGLY1: A fascinating, multifunctional molecule

Cited by 7 publications

References 67 publications

Transcription factor Nrf1 regulates proteotoxic stress-induced autophagy

Transcription factor Nrf1 regulates proteotoxic stress-induced autophagy

Structural basis of sugar recognition by SCF^FBS2 ubiquitin ligase involved in NGLY1 deficiency

ELISA-based highly sensitive assay system for the detection of endogenous NGLY1 activity

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NGLY1: A fascinating, multifunctional molecule

Cited by 7 publications

References 67 publications

Transcription factor Nrf1 regulates proteotoxic stress-induced autophagy

Transcription factor Nrf1 regulates proteotoxic stress-induced autophagy

Structural basis of sugar recognition by SCFFBS2 ubiquitin ligase involved in NGLY1 deficiency

ELISA-based highly sensitive assay system for the detection of endogenous NGLY1 activity

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Structural basis of sugar recognition by SCF^FBS2 ubiquitin ligase involved in NGLY1 deficiency