Uncovering non-autonomous mechanisms of control over translational attenuation during heat shock in the metazoan C. elegans

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The initiation of translation is an important point of control in the response of cells to environmental stress. Stress conditions activate stress-responsive kinases that inhibit translation initiation by phosphorylating the alpha subunit of the eukaryotic initiation factor 2 (eIF2α) which results in polysome disassembly and subsequent attenuation of translation. In addition to attenuating translation, stressful environments also activate the transcription of protective molecular chaperones or heat shock proteins (HSPs). One of the major recent developments in the understanding of stress responses is the discovery that the transcriptional expression of chaperones during stress is not triggered autonomously by cells undergoing macromolecular damage, but is instead cell non-autonomously orchestrated by the nervous system. However, it is not known whether translational attenuation across the different cells of a metazoan is also coordinated through similar cell-cell signaling pathways that modulate transcription. In ongoing studies, we have found that although transcription of chaperones and translational attenuation occur independent of each other upon heat shock, as with the transcriptional upregulation of chaperone gene expression, the phosphorylation of eIF2α upon heat stress in C. elegans is dependent on the serotonergic system. These data suggest that serotonergic control over eIF2α phosphorylation may act to integrate transcriptional and translational responses to stress across cells of an organism. This is the hypothesis we aim to test in this proposal. Specifically, we will test (1) how translation attenuation is coupled to neuronal serotonin release and (2) whether translation attenuation is coordinated with HSP upregulation through neuronal 5-HT release. We anticipate that these studies will fill a critical gap in knowledge regarding the coordination of translational upon stress between tissues of a metazoan. These studies will therefore be important for understanding how stress contributes to the progression of metabolic and neurodegenerative diseases and allow the development of new strategies for diagnosis and treatment.