Poster abstracts
Poster number 15 submitted by Max Baymiller
tRNA synthetase activity is required for stress-induced RNP granule assembly
Max Baymiller (Department of Human Genetics, University of Michigan), Stephanie L. Moon (Department of Human Genetics, University of Michigan)
Abstract:
During the cellular response to stress, translation initiation is suppressed via phosphorylation of eIF2α and non-translating mRNAs condense into RNP granules including stress granules and P-bodies. The stress response is active in many diseases including neuropathies caused by mutations in tRNA synthetases, where preventing the stress response is therapeutic. We hypothesized that tRNA synthetase activity is required for stress-induced RNP granule formation by facilitating ribosome runoff. We found that despite P-eIF2α induction by tRNA synthetase inhibitors, stress granule and P-body formation was inhibited. Formation of these RNP granules was rescued upon mRNA release from ribosomes by puromycin. tRNA synthetase activity was also required for arsenite-induced stress granules, further indicating loss of tRNA charging traps mRNAs within polysomes during stress. We observed ribosome-associated quality control factor ZNF598 was activated upon tRNA synthetase inhibition, an indication of ribosome collisions. Yet, ZNF598 depletion did not increase P-eIF2α levels or further decrease stress granules, suggesting ribosome collisions are a minor contributor to tRNA charging stress. Together, these results show that tRNA synthetases are critical for mRNA to cycle from the translating pool into stress-induced RNP granules. Defects in translation elongation that occur in other stresses such as UV and amino acid starvation may also impair RNP granule assembly in this manner. Identifying molecular mechanisms of ribosome rescue that enable RNP granule formation could inform therapeutics for diseases associated with tRNA synthetases or tRNA metabolism.
Keywords: stress granule, tRNA