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Dynamic eIF3a O-GlcNAcylation controls translation reinitiation during nutrient stress
Xin Erica Shu1, Yuanhui Mao1, Longfei Jia1
1Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA.
Nature Chemical Biology
|December 10, 2021
Summary
Nutrient starvation triggers O-GlcNAc modification changes in eukaryotic initiation factor 3 (eIF3), promoting ribosome reinitiation for activating transcription factor 4 (ATF4) synthesis. This links nutrient stress to translational control.
Area of Science:
- Molecular Biology
- Cellular Biology
- Biochemistry
Background:
- Eukaryotic messenger RNAs (mRNAs) often contain upstream open reading frames (uORFs) that influence translation.
- Ribosome reinitiation after uORF translation is a key regulatory mechanism.
- The role of initiation factors, like eukaryotic initiation factor 3 (eIF3), in ribosome elongation and reinitiation remains unclear.
Purpose of the Study:
- To investigate the regulation of eIF3 association with elongating ribosomes.
- To explore the role of post-translational modifications in controlling ribosome recycling versus reinitiation.
- To elucidate the mechanism linking nutrient stress to translational reprogramming.
Main Methods:
- Utilized CRISPR genome editing to modify the eIF3a protein.
- Investigated O-linked N-acetylglucosamine (O-GlcNAc) modification dynamics of eIF3a.
- Analyzed ribosome retention and activating transcription factor 4 (ATF4) reinitiation under varying nutrient conditions.
Main Results:
- eIF3a undergoes dynamic O-GlcNAc modification in response to nutrient starvation.
- Stress-induced de-O-GlcNAcylation enhances eIF3 retention on elongating ribosomes.
- Disruption of eIF3a modification promotes ATF4 reinitiation even in nutrient-rich conditions.
Conclusions:
- Dynamic O-GlcNAc modification of eIF3a regulates ribosome recycling and reinitiation.
- This mechanism connects nutrient stress sensing to translational control via ATF4.
- Findings provide insight into balancing translation efficiency and stress response.
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