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Cytosolic GDH1 degradation restricts protein synthesis to sustain tumor cell survival following amino acid deprivation.

Authors :
Shao J
Shi T
Yu H
Ding Y
Li L
Wang X
Wang X
Source :
The EMBO journal [EMBO J] 2021 Oct 18; Vol. 40 (20), pp. e107480. Date of Electronic Publication: 2021 Jul 16.
Publication Year :
2021

Abstract

The mTORC1 pathway plays key roles in regulating various biological processes, including sensing amino acid deprivation and driving expression of ribosomal protein (RP)-coding genes. In this study, we observed that depletion of glutamate dehydrogenase 1 (GDH1), an enzyme that converts glutamate to α-ketoglutarate (αKG), confers resistance to amino acid deprivation on kidney renal clear cell carcinoma (KIRC) cells. Mechanistically, under conditions of adequate nutrition, GDH1 maintains RP gene expression in a manner dependent on its enzymatic activity. Following amino acid deprivation or mTORC1 inhibition, GDH1 translocates from mitochondria to the cytoplasm, where it becomes ubiquitinated and degraded via the E3 ligase RNF213. GDH1 degradation reduces intracellular αKG levels by more than half and decreases the activity of αKG-dependent lysine demethylases (KDMs). Reduced KDM activity in turn leads to increased histone H3 lysine 9 and 27 methylation, further suppressing RP gene expression and preserving nutrition to support cell survival. In summary, our study exemplifies an economical and efficient strategy of solid tumor cells for coping with amino acid deficiency, which might in the future be targeted to block renal carcinoma progression.<br /> (© 2021 The Authors.)

Subjects

Subjects :
Adenosine Triphosphatases genetics
Adenosine Triphosphatases metabolism
Animals
Carcinoma, Renal Cell metabolism
Carcinoma, Renal Cell mortality
Carcinoma, Renal Cell pathology
Cell Cycle Proteins genetics
Cell Cycle Proteins metabolism
Cell Line, Tumor
DNA-Binding Proteins antagonists & inhibitors
DNA-Binding Proteins genetics
DNA-Binding Proteins metabolism
Epithelial Cells metabolism
Epithelial Cells pathology
Female
Gene Expression Regulation, Neoplastic
Glutamate Dehydrogenase antagonists & inhibitors
Glutamate Dehydrogenase metabolism
Histone Demethylases genetics
Histone Demethylases metabolism
Humans
Jumonji Domain-Containing Histone Demethylases genetics
Jumonji Domain-Containing Histone Demethylases metabolism
Kidney Neoplasms metabolism
Kidney Neoplasms mortality
Kidney Neoplasms pathology
Mice
Mice, Nude
Neoplasm Proteins genetics
Neoplasm Proteins metabolism
Nuclear Proteins antagonists & inhibitors
Nuclear Proteins genetics
Nuclear Proteins metabolism
Poly-ADP-Ribose Binding Proteins genetics
Poly-ADP-Ribose Binding Proteins metabolism
Protein Isoforms genetics
Protein Isoforms metabolism
RNA, Small Interfering genetics
RNA, Small Interfering metabolism
Ribosomal Proteins genetics
Ribosomal Proteins metabolism
Signal Transduction
Survival Analysis
Ubiquitin-Protein Ligases genetics
Ubiquitin-Protein Ligases metabolism
Xenograft Model Antitumor Assays
Carcinoma, Renal Cell genetics
Glutamate Dehydrogenase genetics
Glutamic Acid metabolism
Ketoglutaric Acids metabolism
Kidney Neoplasms genetics

Details

Language :
English
ISSN :
1460-2075
Volume :
40
Issue :
20
Database :
MEDLINE
Journal :
The EMBO journal
Publication Type :
Academic Journal
Accession number :
34269483
Full Text :
https://doi.org/10.15252/embj.2020107480