Ablation of arginylation in the mouse N-end rule pathway: Loss of fat, higher metabolic rate, damaged spermatogenesis, and neurological perturbations

Date

2009

Authors

Brower, Christopher S.
Varshavsky, Alexander

Journal Title

Journal ISSN

Volume Title

Publisher

Public Library of Science

Abstract

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 Ate12/2 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.

Description

Keywords

Protein degradation, Ubiquitin ligases, N-end rule

Citation

This is the published version of an article that is available at https://doi.org/10.1371/journal.pone.0007757. Recommended citation: Brower, C. S., & Varshavsky, A. (2009). Ablation of arginylation in the mouse N-end rule pathway: Loss of fat, higher metabolic rate, damaged spermatogenesis, and neurological perturbations. PLoS ONE, 4(11). This item has been deposited in accordance with publisher copyright and licensing terms and with the author’s permission.

Collections