Conserved Function of Drg GTPases to Promote Protein Synthesis in the Ribosome

Translation is regulated temporally and spatially to ensure proteins are synthesized at the right time and place in the cell. Temporary halting of ribosomal movement along an mRNA during translation (leading to a "paused" ribosome) allows the cell to synchronize protein production in response to internal cues, external signals, subcellular localization, and other regulatory mechanisms. Furthermore, how the cell distinguishes between a functional physiological pause and a harmful pathological stall remains a fundamental question in biology. Here, we report the discovery of a new class of GTPases, Developmentally Regulated GTP-binding (Drg) proteins, that promote protein biosynthesis in the halted ribosome in an evolutionarily conserved manner. We show that the essential bacterial Obg GTPases are distant homologs of eukaryotic and archaeal Drg proteins that are critical for proteostasis. Through in vivo cross-species complementation of cells where ribosomes are induced to pause or stall, we demonstrate the conserved function of Drg proteins to enhance translation in the ribosome in a GTPase-dependent manner. Our data show that bacterial Obg rescues cellular growth and translation in both Saccharomyces cerevisiae and human cells lacking their endogenous Drgs. Furthermore, the presence of Obg-GTP stimulates peptidyl transfer, the key catalytic function of the ribosome, suggesting a possible molecular mechanism underlying their conserved cellular function. This discovery shows that the Drg protein is a new general translation factor that directly affords cells from the three domains of life a new level of regulation.