Thioredoxin activates MKK4-NF{kappa}B pathway in a redox dependent manner to control manganese superoxide dismutase gene expression in endothelial cells [Gene Regulation]

May 31st, 2015 by Kundumani-Sridharan, V., Subramani, J., Das, K. C.

The mitogen-activated protein kinase kinase 4 (MKK4) is activated via phosphorylation of Ser257 and Thr261 by upstream MAP3Ks and activates JNK and p38 MAPKs in response to cellular stress. We show that thioredoxin, a cellular redox protein activates MKK4 via Cys246 and Cys266 residues as mutation of these residues renders MKK4 insensitive to phosphorylation by MAP3Ks, TNFα or Trx. MKK4 is activated in vitro by reduced Trx, but not oxidized Trx in the absence of an upstream kinase, suggesting that auto-phosphorylation of this protein occurs due to reduction of Cys246 and Cys266 by Trx. Additionally, mutation of Cys246 and Cys266 resulted in loss of kinase activity suggesting that redox state of Cys246 and Cys266 is a critical determinant of MKK4 activation. Trx induces MnSOD gene transcription by activating MKK4 via redox control of Cys246 and Cys266, as mutation of these residues abrogates MKK4 activation and MnSOD expression. We further show that MKK4 activates NFκB for its binding to the MnSOD promoter, which leads to AP-1 dissociation followed by MnSOD transcription. Taken together, our studies show that redox status of Cys246 and Cys266 in MKK4 controls its activities independent of MAP3K, demonstrating integration of endothelial redox environment to MAPK signaling.
  • Posted in Journal of Biological Chemistry, Publications
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