NO Spells End for RGS Proteins

Science's STKE  18 Oct 2005:
Vol. 2005, Issue 306, pp. tw362
DOI: 10.1126/stke.3062005tw362

Many biological processes are regulated by changes in the abundance of the gaseous molecule nitric oxide (NO). In particular, NO has therapeutically beneficial effects on heart function. However, the mechanisms by which NO influences cellular function are not fully understood. Hu et al. provide evidence that NO promotes arginylation (conjugation with an arginine residue) of N-terminal Cys residues present in certain proteins. Such modification of proteins marks them for ubiquitin-dependent degradation. Among the 30 or so mammalian proteins that contain the sequence susceptible to this modification are three RGS [regulator of G protein (heterotrimeric guanine nucleotide-binding protein) signaling] proteins. The abundance of these proteins was increased in mouse embryos lacking the arginyl transferase that mediates their arginylation. The authors suspected that alterations in oxidation of the N-terminal Cys residue in these proteins (which is required for its arginylation) might be mediated by NO. Indeed, in cells treated with pharmacological agents that increase or decrease NO concentrations, the abundance of a tagged form of exogenously expressed RGS4 was increased or decreased, respectively. Such NO-dependent arginylation of RGS4 was also demonstrated in vitro. By controlling the abundance of RGS proteins, this mechanism appears to allow NO signaling to regulate signaling from G protein-coupled receptors. Mice lacking the arginine transferase die of cardiovascular defects. Although other mechanisms are also known to mediate NO's actions on the heart, the authors propose that arginine transferases may provide another, potentially selective target to reproduce the known beneficial effects of drugs that enhance NO concentrations.

R.-G. Hu, J. Sheng, X. Qi, Z. Xu, T. T. Takahashi, A. Varshavsky, The N-end rule pathway as a nitric oxide sensor controlling the levels of multiple regulators. Nature 437, 981-986 (2005). [PubMed]