ROS are involved in cell signaling:
Activation of the TNF receptor triggers ROS production, enhancing phosphorylation (P) of inhibitor of NF-κB (IκB), leading to ubiquitylation (Ub) of IκB and its proteasomal degradation. Freed NF-κB translocates to the nucleus to initiate transcription. ROS also triggers oxidative glutathionylation of NF-κB, reducing its DNA binding affinity. In normoxia, prolyl hydroxylases (PHs) hydroxylate HIF1α, allowing it to be recognized by the E3 ligase VHL tumour-suppressor protein and promoting its proteasomal degradation. Under hypoxia ROS production increases, inhibiting PH and leading to accumulation of HIF1α, which translocates to the nucleus to mediate gene transcription. ROS production by NADPH oxidases (NOXs) following receptor activation inhibits protein tyrosine phosphatases (PTPs), leading to increased tyrosine kinases (TKs) phosphorylation and signal transduction. ATM kinase is directly activated by ROS via disulphide bond-mediated homodimerization, leading to phosphorylation of heat shock protein 27 and subsequent activation of G6PD. The resulting NADPH increase contributes to maintenance of cellular redox homeostasis. ROS-mediated disulphide bonding can also lead to heterodimerization, as seen between FOXO transcription factors & p300/CBP acetyltransferase, leading to acetylation of FOXO proteins and activation of gene transcription.
Regulation of transcription:
Induction of transcription of the VEGF gene by HIF1α is enhanced through dynein-mediated perinuclear localization of mitochondria (mt). Mt-derived ROS diffuse into the nucleus and promote oxidation of guanine nucleotides, forming 8-oxoguanine (8OG). Transcriptional regulation downstream of activation of receptors (e.g. AR, OR, MYC) also involves ROS DNA modification. 8OG recruit base excision repair machinery and DNA breaks generated by 8OG DNA glycosylase 1 (OGG1) enable activation of transcription.
Nathan, C. & Cunningham-Bussel, A. Nat Rev Immunol. 2013;13:349-361.
DNA, deoxyribonucleic acid; cAMP, cyclic adenosine monophosphate; HIF1α, hypoxia inducible factor 1-alpha; NF-κB, nuclear factor kappa B; ROS, reactive oxygen species; TNFR, tumor necrosis factor receptor; VEGF, vascular endothelial growth factor.
