A new cell stress survival mechanism has been identified that is initiated during sustained stress and acts additionally to and independently of the classically understood integrated stress response pathways. This work from the group of Prof Xiang-Lei Yang at The Scripps Institute shows a direct link between reaction-limiting substrate availability for an enzyme, its nuclear translocation and inhibition of protein translation genes.
Both mechanisms aim to protect the cell by limiting protein translation, with feedback control systems to avoid extended abolition. However, unlike the classical mTOR an eIF2a pathways where an early suppression acts on components of translation initiation, this new independent mechanism acts directly on translational genes, upon sustained/prolonged cell stress.
The key component in this response to prolonged cell stress is tyrosyl-tRNA synthase (TyrRS) which operates as a sensor of the paucity of energy (ATP) and/or substrate (tyrosine) and, therein unoccupied by tRNA, is translocated to the nucleus where it binds directly to translation genes or complexes with other regulatory elements which bind to translational genes to inhibit protein translation (and has elsewhere been shown to activate DNA repair genes).
The early/acute response has a positive feedback element that re-initiates protein translation since its abrogation is not sustainable, otherwise apoptosis would occur. Yet this does rely upon the rapid resolution of the stress otherwise cell death would still ultimately result. Here then, under continued stress the Tyr-RS mechanism comes into play to further inhibit translation, now at the gene expression level while elegantly inhibiting its own gene expression and that of other aminoacyl-tRNA synthetases (aaRS). The latter opens an interesting question as to whether other aaRSs behave in a similar manner, act synergistically or perhaps even to further fine tune the system.
DRAQ5™ was utilised as nuclear counterstain to determine the impact of acetylation / deacetylation on the TyrRS nuclear localisation sequence (NLS) - WT and two mutants by GFP tagging and fluorescence microscopy. Thank you to the authors for this choice of reagent in such fascinating work on fundamental cell biology. Where can I buy DRAQ5?
Reference:
Jones, Julia A., et al. "Nuclear translocation of an aminoacyl-tRNA synthetase may mediate a chronic “integrated stress response”." Cell Reports 42.6 (2023).
