S-nitrosylation in the regulation of gene transcription

Abstract

Background: Post-translational modification of proteins by S-nitrosylation serves as a major mode of signaling in mammalian cells and a growing body of evidence has shown that transcription factors and their activating pathways are primary targets. S-nitrosylation directly modifies a number of transcription factors, including NF-κB, HIF-1, and AP-1. In addition, S-nitrosylation can indirectly regulate gene transcription by modulating other cell signaling pathways, in particular JNK kinase and ras.

Scope of review: The evolution of S-nitrosylation as a signaling mechanism in the regulation of gene transcription, physiological advantages of protein S-nitrosylation in the control of gene transcription, and discussion of the many transcriptional proteins modulated by S-nitrosylation is summarized.

Major conclusions: S-nitrosylation plays a crucial role in the control of mammalian gene transcription with numerous transcription factors regulated by this modification. Many of these proteins serve as immunomodulators, and inducible nitric oxide synthase (iNOS) is regarded as a principal mediatiator of NO-dependent S-nitrosylation. However, additional targets within the nucleus (e.g. histone deacetylases) and alternative mechanisms of S-nitrosylation (e.g. GAPDH-mediated trans-nitrosylation) are thought to play a role in NOS-dependent transcriptional regulation.

General significance: Derangement of SNO-regulated gene transcription is an important factor in a variety of pathological conditions including neoplasia and sepsis. A better understanding of protein S-nitrosylation as it relates to gene transcription and the physiological mechanisms behind this process is likely to lead to novel therapies for these disorders. This article is part of a Special Issue entitled Regulation of Cellular Processes by S-nitrosylation.

Fig. 1

S-nitrosylation in NF-κB signaling. Engagement of cell surface receptors [TNFα (TNFR1), IL-1 (IL-1R), TLR-4, growth factor receptor] leads to the recruitment of receptor-associated proteins, several of which, p21ras, epidermal growth factor (EGF) tyrosine kinase, and MyD88, are regulated by S-nitrosylation. TNFR1 also activates the JNK kinase pathway which can enhance NF-κB signaling via the effects of the E3 ubiquitin ligase SCF-β-TrCP and IκBα proteasomal degradation. S-nitrosylation of two JNK pathway proteins, apoptosis signaling kinase 1 (ASK1) and JNK1, inhibit SCF-β-TrCP activation. Phosphorylation of IκBα, which targets it for ubiquitin-mediated proteasomal degradation, is inhibited by SNO modification of the IκBα kinaseβ (IKKβ) subunit or the ras pathway protein Akt. DNA binding of the NF-κB activating heterodimer (p50-p65) is inhibited by S-nitrosylation of either subunit. Thioredoxin can denitrosylate NF-κB p50-p65 directly or indirectly via activation of Ref-1 in the nucleus. S-nitrosylation, in turn, inhibits the activity of thioredoxin and Ref-1.

Fig. 2

S-nitrosylation in HIF-1 signaling. NO inhibits proline hydroxylases (PHD) under normoxic conditions. S-nitrosylation of HIF-1α at cysteine-533 (C533) interferes with binding to the von Hippel Lindau (VHL) protein preventing its ubiquitination and proteasomal degradation. HIF-1α interacts with HIF-1β and the complex translocates to the nucleus to activate genes such as VEGF. HIF-1α also undergoes S-nitrosylation at cysteine-800 (C800) facilitating binding of the transcriptional co-factor p300/CREBwhich also increases HIF-1-dependent transcription.