Ablation of arginylation in the mouse N-end rule pathway: loss of fat, higher metabolic rate, damaged spermatogenesis, and neurological perturbations.
In the N-end rule pathway of protein degradation, the destabilizing activity of N-terminal Asp, Glu or (oxidized) Cys residues requires their conjugation to Arg, which is recognized directly by pathway's ubiquitin ligases. N-terminal arginylation is mediated by the Ate1 arginyltransferase, whose physiological substrates include the Rgs4, Rgs5 and Rgs16 regulators of G proteins. Here, we employed the Cre-lox technique to uncover new physiological functions of N-terminal arginylation in adult mice. We show that postnatal deletion of mouse Ate1 (its unconditional deletion is embryonic lethal) causes a rapid decrease of body weight and results in early death of approximately 15% of Ate1-deficient mice. Despite being hyperphagic, the surviving Ate1-deficient mice contain little visceral fat. They also exhibit an increased metabolic rate, ectopic induction of the Ucp1 uncoupling protein in white fat, and are resistant to diet-induced obesity. In addition, Ate1-deficient mice have enlarged brains, an enhanced startle response, are strikingly hyperkinetic, and are prone to seizures and kyphosis. Ate1-deficient males are also infertile, owing to defects in Ate1(-/-) spermatocytes. The remarkably broad range of specific biological processes that are shown here to be perturbed by the loss of N-terminal arginylation will make possible the dissection of regulatory circuits that involve Ate1 and either its known substrates, such as Rgs4, Rgs5 and Rgs16, or those currently unknown.
Brower
Christopher S
CS
Division of Biology, California Institute of Technology, Pasadena, CA, USA.
Varshavsky
Alexander
A
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000737:chemistry*; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D005838:Genotype; D007700:Kinetics; D008297:Male; D051379:Mice; D008957:Models, Genetic; D008959:Models, Neurological; D017434:Protein Structure, Tertiary; D012640:Seizures / Q000378:metabolism; D013090:Spermatocytes / Q000378:metabolism; D013091:Spermatogenesis
D001120:Arginine; D019204:GTP-Binding Proteins