Conserved metabolite regulation of stress granule assembly via AdoMet

Stress granules (SGs) are evolutionarily conserved condensates of ribonucleoproteins that assemble in response to metabolic stresses. Because aberrant SG formation is associated with amyotrophic lateral sclerosis (ALS), understanding the connection between metabolic activity and SG composition can p...

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Bibliographic Details
Published in:The Journal of cell biology 2020-08, Vol.219 (8)
Main Authors: Begovich, Kyle, Vu, Anthony Q, Yeo, Gene, Wilhelm, James E
Format: Article
Language:English
Subjects:
Amyotrophic Lateral Sclerosis - genetics
Amyotrophic Lateral Sclerosis - metabolism
Amyotrophic Lateral Sclerosis - pathology
Cytoplasmic Granules - genetics
Cytoplasmic Granules - metabolism
Cytoplasmic Granules - pathology
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Energy Metabolism
HeLa Cells
Humans
Metabolism
Methionine Adenosyltransferase - genetics
Methionine Adenosyltransferase - metabolism
Motor Neurons - drug effects
Motor Neurons - metabolism
Motor Neurons - pathology
RNA biology
S-Adenosylmethionine - metabolism
S-Adenosylmethionine - pharmacology
Saccharomyces cerevisiae - genetics
Saccharomyces cerevisiae - metabolism
Saccharomyces cerevisiae Proteins - genetics
Saccharomyces cerevisiae Proteins - metabolism
Stress, Physiological
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Summary:Stress granules (SGs) are evolutionarily conserved condensates of ribonucleoproteins that assemble in response to metabolic stresses. Because aberrant SG formation is associated with amyotrophic lateral sclerosis (ALS), understanding the connection between metabolic activity and SG composition can provide therapeutic insights into neurodegeneration. Here, we identify 17 metabolic enzymes recruited to yeast SGs in response to physiological growth stress. Furthermore, the product of one of these enzymes, AdoMet, is a regulator of SG assembly and composition. Decreases in AdoMet levels increase SG formation, while chronic elevation of AdoMet produces SG remnants lacking proteins associated with the 5' end of transcripts. Interestingly, acute elevation of AdoMet blocks SG formation in yeast and motor neurons. Treatment of ALS-derived motor neurons with AdoMet also suppresses the formation of TDP-43-positive SGs, a hallmark of ALS. Together, these results argue that AdoMet is an evolutionarily conserved regulator of SG composition and assembly with therapeutic potential in neurodegeneration.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.201904141