eIF3a Destabilization and TDP-43 Alter Dynamics of Heat-Induced Stress Granules

Area of Science:

• Cell biology
• Molecular biology
• Biochemistry

Background:

• Stress granules (SGs) are dynamic cellular structures that form in response to stress, sequestering mRNA and proteins to regulate gene expression.
• In yeast, SGs containing the translation initiation factor Rpg1 typically form only under severe heat shock (HS) at 46 °C.
• Understanding SG formation and disassembly is crucial for cellular stress response and disease mechanisms.

Purpose of the Study:

• To investigate the role of Rpg1 destabilization in SG assembly at lower temperatures.
• To characterize the properties and cellular associations of SGs formed under moderate HS.
• To explore the effect of human TDP-43 on SG disassembly and cellular recovery in yeast.

Main Methods:

• Yeast genetics and molecular biology techniques.
• Microscopy to visualize stress granule formation and localization.
• Analysis of protein-RNA interactions and cellular stress response.

Main Results:

• A destabilized Rpg1 variant (Rpg1-3) induced SG assembly at a moderate HS of 42 °C.
• These SGs contained translation machinery components, associated with P-bodies, ER, mitochondria, and ERMES.
• Human TDP-43 reversed the delayed disassembly of SGs after robust HS and promoted cell regrowth.

Conclusions:

• Rpg1 destabilization provides a mechanism for SG formation at reduced stress levels.
• Yeast SGs associated with various organelles, including ERMES, highlighting complex cellular interactions.
• Yeast SGs serve as a valuable model for studying TDP-43 function in SG disassembly and its implications for neurodegenerative diseases like ALS.