Abstract
Stress granules (SGs) are membrane-less assemblies arising upon various stresses in eukaryotic cells. They sequester mRNAs and proteins from stressful conditions and modulate gene expression to enable cells to resume translation and growth after stress relief. SGs containing the translation initiation factor eIF3a/Rpg1 arise in yeast cells upon robust heat shock (HS) at 46 °C only. We demonstrate that the destabilization of Rpg1 within the PCI domain in the Rpg1-3 variant leads to SGs assembly already at moderate HS at 42 °C. These are bona fide SGs arising upon translation arrest containing mRNAs, which are components of the translation machinery, and associating with P-bodies. HS SGs associate with endoplasmatic reticulum and mitochondria and their contact sites ERMES. Although Rpg1-3-labeled SGs arise at a lower temperature, their disassembly is delayed after HS at 46 °C. Remarkably, the delayed disassembly of HS SGs after the robust HS is reversed by TDP-43, which is a human protein connected with amyotrophic lateral sclerosis. TDP-43 colocalizes with HS SGs in yeast cells and facilitates cell regrowth after the stress relief. Based on our results, we propose yeast HS SGs labeled by Rpg1 and its variants as a novel model system to study functions of TDP-43 in stress granules disassembly.
Highlights
The cell response to robust environmental stresses is accompanied by the formation of stress granules (SGs) as a defense to minimize stress-related damage and to modulate gene expression to promote cell survival
The disassembly of heat shock (HS) SGs formed at 46 ◦C in yeast cells is facilitated by the presence of TDP-43, which is a human protein implicated in Amyotrophic lateral sclerosis (ALS) pathologies
The intriguing question is how SGs arise upon the translational arrest at 42 ◦C in rpg1-3 cells? Is it an additional condensation of the translation machinery components on sites pre-determined by eEF3/Yef3 and Dcp2 [8]? Our results demonstrate that Yef3 is included in 42 ◦C-HS SGs that closely associate with Dcp2-labeled P-bodies similar to robust HS SGs [6]
Summary
The cell response to robust environmental stresses is accompanied by the formation of stress granules (SGs) as a defense to minimize stress-related damage and to modulate gene expression to promote cell survival. SGs are dynamic membrane-less ribonucleoprotein (RNP) assemblies arising upon translational arrest, containing mRNAs, components of the translation machinery, RNA-binding, and non-RNA-binding proteins [1,2,3]. The composition of SGs depends on the type and duration of the stress, but the translation initiation factor eIF3 is a hallmark of canonical SGs [3,4,5,6,7,8]. MRNAs present in SGs were thought to be in a silent, translationally repressed state. Some mRNAs can undergo translation, even when localized in SGs induced by oxidative stress in HeLa cells [9]. P-bodies are RNPs characterized by mRNAs and proteins linked to RNA metabolism [12,13]. In contrast to SGs, P-bodies are present at physiological conditions [14] and never contain eIF3
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