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C12. Signal Transduction and Reactive Oxygen Species

We have previously shown that the redox state of a cells affects protein folding and disulfide bond formation as well as the health of a cell.  It should not be surprising then that the redox state of a cell is regulated and also that the redox state of a cell regulates cell activity.   Consider a reactive ROS and potent oxidizing agent, hydrogen peroxide.  We have described the potential deleterious effects of this molecules on lipids, nucleic acids, and proteins.  At the same time, it can act to protect a cell.  This is clearly seen in the case of immune cells like neutrophils, which can engulf microorganisms, and kill them, in part through generation of ROS like hydrogen peroxide formed after an oxidative burst of activity.  Hydrogen peroxide is generated in neutrophils through the action of NADPH oxidase (Nox), which catalyzes the production of NADP and H2O2 from NADPH + O2.   The neutrophil must be protected from the effects of the H2O2 which rises to mM concentrations, but destruction of H2O2 must be minimized while it acts to kill the microorganism.  Nox, a membrane protein found on the cell membrane, produces H2O2.  It's also found in phagosomes, which contain Nox from the cell membrane.  For H2O2 to regulate cell activity, it must translocate into the cytoplasm.  Cytoplasmic H2O2 has been shown to regulate signal transduction pathways by chemically modifying Cys residues in key signal transduction proteins.  Phosphatases, which contain an active site Cys in a Cys-XXXX-R catalytical loop, can be reversibly oxidized by H2O2.  The Arg side chain decreases the pKa of the active site Cys, making it a better nucleophile toward phospho-tyrosine substrates and more susceptible to H2O2oxidation.   This inhibition, which can be reversed on addition of thiols, is also observed on stimulation of cells with various external signaling ligands and leads to an  increase in the phosphorylation state of proteins, altering signal transduction pathways.  These changes correlate with increased cytoplasmic H2O2.    In addition, it has been shown the oxidation of two Cys side chains in Src, a protein kinase, activated the enzyme in a process that correlates with the appearance of H2O2. 

For these H2O2-dependent events to occur, the H2O2 must be protected from enzymes like catalase, but more importantly peroxiredoxin, which is found in the cytoplasm. These enzymes have been shown to react with two H2O2 molecules, which inactivate them as one of the two Cys is coverted from RSH to RSO2-. (Rhee, 2006)   Another eukaryotic protein, sulfiredoxin, can reverse this inhibition.

Nox is assembled in highly specific subcellular regions of the membrane such as lipid rafts and focal complexes(between the cell and the extracellular matrix).  H2O2 is imported into the cell.  For some membranes H2O2 is easily diffused across the membrane, but recent studies have shown other membranes lack this permeability.  In this case aquaporin may regulate the transfer.  Furthermore, Nox protein assembly has been discovered in organelle membranes such as the endoplasmic reticulum and nucleus.  H2O2 produced in these regions is held within the lumen of the organelle.

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