Survival from hypoxia in C. elegans by inactivation of aminoacyl-tRNA synthetases.
Hypoxia is important in a wide range of biological processes, such as animal hibernation and cell survival, and is particularly relevant in many diseases. The sensitivity of cells and organisms to hypoxic injury varies widely, but the molecular basis for this variation is incompletely understood. Using forward genetic screens in Caenorhabditis elegans, we isolated a hypoxia-resistant reduction-of-function mutant of rrt-1 that encodes an arginyl-transfer RNA (tRNA) synthetase, an enzyme essential for protein translation. Knockdown of rrt-1, and of most other genes encoding aminoacyl-tRNA synthetases, rescued animals from hypoxia-induced death, and the level of hypoxia resistance was inversely correlated with translation rate. The unfolded protein response was induced by hypoxia and was required for the hypoxia resistance of the reduction-of-function mutant of rrt-1. Thus, translational suppression produces hypoxia resistance, in part by reducing unfolded protein toxicity.
Anderson
Lori L
LL
Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Mao
Xianrong
X
Scott
Barbara A
BA
Crowder
C Michael
CM
D000595:Amino Acid Sequence; D000604:Amino Acyl-tRNA Synthetases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001126:Arginine-tRNA Ligase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D017173:Caenorhabditis elegans / Q000166:cytology / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia; D008136:Longevity; D008969:Molecular Sequence Data; D032342:Muscle Cells / Q000502:physiology; D009154:Mutation; D009474:Neurons / Q000502:physiology; D010100:Oxygen / Q000502:physiology*; D010101:Oxygen Consumption; D014176:Protein Biosynthesis; D017510:Protein Folding; D034622:RNA Interference; D019076:Transgenes
D029742:Caenorhabditis elegans Proteins; D000604:Amino Acyl-tRNA Synthetases; D001126:Arginine-tRNA Ligase; D010100:Oxygen