Translation Machinery in Health & Disease - Protein Synthesis and Beyond

Translation is the process of creating proteins using information stored in messenger RNAs. Intriguingly, over the last decade, components of the eukaryotic translation machinery have emerged as a new class of regulatory proteins with widespread functions beyond their classic role in protein synthesis in the cytoplasm. These surprising new functions are associated with cytoplasmic, nuclear, mitochondrial and extracellular activities, birthing a new field of biology with broad physiological significance.

For example, tRNA binding to cytochrome c inhibits apoptosis; tRNA-derived fragments signal in stress-induced responses and function as microRNAs in modulating gene expression; leucine-tRNA synthetase acts as an amino acid sensor for the mTOR-signaling pathway; lysine-tRNA synthetase mediates immune responses by producing the second messenger diadenosine tetraphosphate. Although tRNA and aminoacyl-tRNA synthetases serve as prominent examples, the regulatory functions of the translation apparatus clearly extend well beyond them.

Ribosomal proteins RPL11 and RPL5 bind and inhibit MDM2 to trigger p53 activation. Elongation factor eEF1A plays a central role in the nuclear export of proteins. Compared with molecules that specialize in regulation and signaling, components of the translation apparatus provide homeostatic regulation at multiple levels as a result of their multi-functionalities. These regulatory activities result from the evolution of these ancient molecules and are critical for the development, adaptation and maintenance of higher organisms.

The translation apparatus has myriad disease connections. Mutations in genes for tRNAs and tRNA synthetases are linked to neurodegeneration and type 2 diabetes; genes encoding ribosomal proteins are mutated in 50% of Diamond-Blackfan Anemia patients; autoantibodies against tRNA synthetases are the hallmark of a chronic autoimmune disorder—antisynthetase syndrome; tRNA, tRNA synthetases and ribosomal proteins are associated with tumorigenesis; specific tRNAs and elongation factor eEF1A and eEF1G are critical for HIV viral reverse transcription; and alterations in the translation apparatus are a central feature of viral infections.

Because of the wide distribution of the functions of the translation apparatus and their involvement in a broad spectrum of diseases, the goal of this conference is to establish a platform to bring together, for the first time, scientists and clinicians from various fields to share their knowledge and to foster collaborations that would lead to a more complete understanding of the translation apparatus and its connections to disease. The conference will be focused on the translation apparatus in eukaryotic cells and will be composed of three main areas: i) new functions of components of the translation apparatus and their mechanisms; ii) disease connections of the translation apparatus and its components and iii) potential therapeutic applications based on insights from basic mechanistic studies.