2024年 医学诺奖得主Gary Ruvkun最新论文

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• 1. Mutations in nucleotide metabolism genes bypass proteasome defects in png-1/NGLY1-deficient Caenorhabditis elegans.

  Katherine S Yanagi,Briar Jochim,Sheikh Omar Kunjo,Peter Breen,Gary Ruvkun,Nicolas Lehrbach

  Basic Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America.

  PLoS Biol (P 1545-7885 E 1544-9173) H指数：234 2024 年 22 卷 7 期 e3002720 页

  PMID：38991033 相似文献

  文摘 DOI链接 Public Library of Science

• 2. CMTR-1 RNA methyltransferase mutations activate widespread expression of a dopaminergic neuron-specific mitochondrial complex I gene.

  Joshua D Meisel,Presli P Wiesenthal,Vamsi K Mootha,Gary Ruvkun

  Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA.

  vamsi@hms.harvard.edu

  Curr Biol (P 1879-0445 E 0960-9822) H指数：290 2024 年 34 卷 12 期 2728-2738.e6 页

  PMID：38810637 相似文献

  文摘 DOI链接 Elsevier Science

• 3. Hypoxia and intra-complex genetic suppressors rescue complex I mutants by a shared mechanism.

  Joshua D Meisel,Maria Miranda,Owen S Skinner,Presli P Wiesenthal,Sandra M Wellner,Alexis A Jourdain,Gary Ruvkun,Vamsi K Mootha

  Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA.

  ruvkun@molbio.mgh.harvard.edu

  Cell (P 1097-4172 E 0092-8674) H指数：705 2024 年 187 卷 3 期 659-675.e18 页

  PMID：38215760 相似文献

  文摘 DOI链接 Elsevier Science

原文

https://pubmed.ncbi.nlm.nih.gov/38991033/

PLoS Biol

. 2024 Jul 11;22(7):e3002720.

 doi: 10.1371/journal.pbio.3002720. eCollection 2024 Jul.

Mutations in nucleotide metabolism genes bypass proteasome defects in png-1/NGLY1-deficient Caenorhabditis elegans

Katherine S Yanagi 1, Briar Jochim 1, Sheikh Omar Kunjo 1, Peter Breen 2, Gary Ruvkun 2 3, Nicolas Lehrbach 1

Affiliations expand

• PMID: 38991033

•  

• PMCID: PMC11265709

•  

• DOI: 10.1371/journal.pbio.3002720

Abstract

The conserved SKN-1A/Nrf1 transcription factor regulates the expression of proteasome subunit genes and is essential for maintenance of adequate proteasome function in animal development, aging, and stress responses. Unusual among transcription factors, SKN-1A/Nrf1 is a glycoprotein synthesized in the endoplasmic reticulum (ER). N-glycosylated SKN-1A/Nrf1 exits the ER and is deglycosylated in the cytosol by the PNG-1/NGLY1 peptide:N-glycanase. Deglycosylation edits the protein sequence of SKN-1A/Nrf1 by converting N-glycosylated asparagine residues to aspartate, which is necessary for SKN-1A/Nrf1 transcriptional activation of proteasome subunit genes. Homozygous loss-of-function mutations in the peptide:N-glycanase (NGLY1) gene cause NGLY1 deficiency, a congenital disorder of deglycosylation. There are no effective treatments for NGLY1 deficiency. Since SKN-1A/Nrf1 is a major client of NGLY1, the resulting proteasome deficit contributes to NGLY1 disease. We sought to identify targets for mitigation of proteasome dysfunction in NGLY1 deficiency that might indicate new avenues for treatment. We isolated mutations that suppress the sensitivity to proteasome inhibitors caused by inactivation of the NGLY1 ortholog PNG-1 in Caenorhabditis elegans. We identified multiple suppressor mutations affecting 3 conserved genes: rsks-1, tald-1, and ent-4. We show that the suppressors act through a SKN-1/Nrf-independent mechanism and confer proteostasis benefits consistent with amelioration of proteasome dysfunction. ent-4 encodes an intestinal nucleoside/nucleotide transporter, and we show that restriction of nucleotide availability is beneficial, whereas a nucleotide-rich diet exacerbates proteasome dysfunction in PNG-1/NGLY1-deficient C. elegans. Our findings suggest that dietary or pharmacological interventions altering nucleotide availability have the potential to mitigate proteasome insufficiency in NGLY1 deficiency and other diseases associated with proteasome dysfunction.

Copyright: © 2024 Yanagi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Suppressors of bortezomib sensitivity in…

Fig 2. The suppressors act by a…

Fig 3. The suppressors enhance proteostasis and…

Fig 4. Intestinal ENT-4 and nucleotide biosynthesis…

Fig 5. Increased dietary nucleotide availability enhances…

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MeSH terms

• Animals

• Caenorhabditis elegans Proteins* / genetics

• Caenorhabditis elegans Proteins* / metabolism

• Caenorhabditis elegans* / genetics

• Caenorhabditis elegans* / metabolism

• Congenital Disorders of Glycosylation / genetics

• Congenital Disorders of Glycosylation / metabolism

• DNA-Binding Proteins / genetics

• DNA-Binding Proteins / metabolism

• Glycosylation

• Mutation*

• Nucleotides / genetics

• Nucleotides / metabolism

• Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase / deficiency

• Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase / genetics

• Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase / metabolism

• Proteasome Endopeptidase Complex* / genetics

• Proteasome Endopeptidase Complex* / metabolism

• Transcription Factors / genetics

• Transcription Factors / metabolism

Substances

• Caenorhabditis elegans Proteins

• DNA-Binding Proteins

• Nucleotides

• Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase

• Proteasome Endopeptidase Complex

• skn-1 protein, C elegans

• Transcription Factors

Related information

• Gene

• Gene (GeneRIF)

• MedGen

• Nucleotide (RefSeq)

• Protein (RefSeq)

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• R35 GM142728/GM/NIGMS NIH HHS/United States

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