Stress Granules as Causes and Consequences of Translation Suppression.

Significance: Stress granules (SGs) are biomolecular condensates that form upon global translation suppression during stress. SGs are enriched in translation factors and messenger RNAs (mRNAs), which they may sequester away from the protein synthesis machinery. While this is hypothesized to remodel the functional transcriptome during stress, it remains unclear whether SGs are a cause, or simply a consequence, of translation repression. Understanding the function of SGs is particularly important because they are implicated in numerous diseases including viral infections, cancer, and neurodegeneration. Recent Advances: We synthesize recent SG research spanning biological scales, from observing single proteins and mRNAs within one cell to measurements of the entire transcriptome or proteome of SGs in a cell population. We use the emerging understanding from these studies to suggest that SGs likely have less impact on global translation, but instead may strongly influence the translation of individual mRNAs localized to them. Critical Issues: Development of a unified model that links stress-induced RNA-protein condensation to regulation of downstream gene expression holds promise for understanding the mechanisms of cellular resilience. Future Directions: Therefore, upcoming research should clarify what influence SGs exert on translation at all scales as well as the molecular mechanisms that enable this. The resulting knowledge will be required to drive discovery in how SGs allow organisms to adapt to challenges and support health or go awry and lead to disease. Antioxid. Redox Signal. 39, 390-409.

Tissue-specific alternative splicing separates the catalytic and cell signaling functions of human leucyl-tRNA synthetase.

The aminoacyl-tRNA synthetases are an ancient and ubiquitous component of all life. Many eukaryotic synthetases balance their essential function, preparing aminoacyl-tRNA for use in mRNA translation, with diverse roles in cell signaling. Herein, we use long-read sequencing to discover a leukocyte-specific exon skipping event in human leucyl-tRNA synthetase (LARS). We show that this highly expressed splice variant, LSV3, is regulated by serine-arginine-rich splicing factor 1 (SRSF1) in a cell-type-specific manner. LSV3 has a 71 amino acid deletion in the catalytic domain and lacks any tRNA leucylation activity in vitro. However, we demonstrate that this LARS splice variant retains its role as a leucine sensor and signal transducer for the proliferation-promoting mTOR kinase. This is despite the exon deletion in LSV3 including a portion of the previously mapped Vps34-binding domain used for one of two distinct pathways from LARS to mTOR. In conclusion, alternative splicing of LARS has separated the ancient catalytic activity of this housekeeping enzyme from its more recent evolutionary role in cell signaling, providing an opportunity for functional specificity in human immune cells.