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Published November 13, 2009 | Published
Journal Article Open

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 ~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.

Additional Information

© 2009 Brower, Varshavsky. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received September 1, 2009; Accepted October 13, 2009; Published November 13, 2009. Editor: Immo A. Hansen, New Mexico State University, United States of America. This study was supported by grants to A.V. from the National Institutes of Health (GM31530 and DK39520), the American Asthma Foundation, and the March of Dimes Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We are grateful to current and former members of the Varshavsky laboratory for their advice and help. We thank R.-G. (Cory) Hu for antibody to Ate1, K. I. Piatkov for helpful discussions, N. V. Malkova for advice and assistance with behavioral tests, S. Pease for advice regarding ES cell manipulation, D. Procissi and K. P. Roos for help with MRI and metabolic rate tests, respectively, and E. Udartseva for assistance with genotyping mouse strains. Author Contributions: Conceived and designed the experiments: CSB AV. Performed the experiments: CSB. Analyzed the data: CSB AV. Contributed reagents/ materials/analysis tools: CSB AV. Wrote the paper: CSB AV.

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August 19, 2023
October 19, 2023