Protein S-nitrosylation in health and disease: a current perspective

Abstract

Protein S-nitrosylation constitutes a large part of the ubiquitous influence of nitric oxide on cellular signal transduction and accumulating evidence indicates important roles for S-nitrosylation both in normal physiology and in a broad spectrum of human diseases. Here we review recent findings that implicate S-nitrosylation in cardiovascular, pulmonary, musculoskeletal and neurological (dys)function, as well as in cancer. The emerging picture shows that, in many cases, pathophysiology correlates with hypo- or hyper-S-nitrosylation of specific protein targets rather than a general cellular insult due to loss of or enhanced nitric oxide synthase activity. In addition, it is increasingly evident that dysregulated S-nitrosylation can not only result from alterations in the expression, compartmentalization and/or activity of nitric oxide synthases, but can also reflect a contribution from denitrosylases, including prominently the S-nitrosoglutathione (GSNO)-metabolizing enzyme GSNO reductase. Finally, because exogenous mediators of protein S-nitrosylation or denitrosylation can substantially affect the development or progression of disease, potential therapeutic agents that modulate S-nitrosylation could well have broad clinical utility.

Fig. 1. NOS-dependent mechanisms of S-nitrosylation

Three principal mechanisms for regulation of NO synthase (NOS)-dependent protein S-nitrosylation and the (patho)physiology associated with the induction or disruption of these mechanisms are shown. (a) Binding of a transcription factor (TF) to NOS promoter induces expression of the gene encoding NOS. (b) (Left) influx into the cytosol of extracellular or internal store-derived Ca²⁺ promotes Ca²⁺-calmodulin (CaM) binding and activation of eNOS and nNOS. Alternatively (right), phosphoinositide-3 kinase (PI3K) activates protein kinase B (Akt), which phosphorylates and activates eNOS. (c) Subcellular compartmentation (co-localization) of NOS and its substrates, which may involve a direct interaction (as in the illustrated case of a membrane-intercalated ion channel) is an important determinant of the target specificity of S-nitrosylation, and dysregulated co-localization can result in hyper- or hypo-S-nitrosylation.

Fig. 2. Regulation of SNO homeostasis by S-nitrosoglutathione reductase (GSNOR)

(a) In cells, the low-mass S-nitrosothiol, S-nitrosoglutathione (GSNO), is in equilibrium with a subset of protein S-nitrosothiols. GSNO is metabolized by the enzyme GSNOR, and cells and tissues lacking GSNOR exhibit increased levels of SNO-proteins. (b) Analyses in GSNOR-knockout mice (GSNOR^−/−) have revealed numerous roles for protein S-nitrosylation. In particular, knockout animals exhibit low systemic vascular resistance and increased cardiac output under basal conditions, and are protected from mocardial infarction and allergen-induced airway hyperreactivity. (c) Mutations in GSNOR, as well as increased airway GSNOR expression and activity, are associated with human asthma.