FIG. 8.

Trx, Txnip, and Grx in MAP kinase and NF-κB signaling. Txnip, whose expression is promoted by glucose via MondoA:MLX signaling and repressed by FOXO1a, was suggested to be a negative regulator of reduced Trx1. Left side: Trx and Grx as negative regulators of apoptosis signal-regulating kinase 1 (ASK1)–ASK1 is a mitogen-activated protein (MAP) kinase kinase kinase that signals downstream to the c-Jun N-terminal kinase (JNK) and the p38 MAP kinase pathways via MAP kinase kinases 3, 4, 6, and 7. Reduced Trx1 and Grx1 can bind to ASK1, leading to an inactive complex. Oxidation of Trx1 and/or Grx1 by various redox signals leads to dissociation of the complex and activation of ASK1. Moreover, the Trx1/ASK1 complex is targeted for ubiquitination and degradation. Right side: Redox regulation of NF-κB activation–the NF-κB subunit p50 contains a cysteine (Cys 62) in its DNA binding site that is susceptible to oxidation. After dissociation of the I-κB/NF-κB complex, which is not only promoted by phosphorylation of I-κB in response to a variety of signals but also inhibited by reduced Trx1, NF-κB is translocated to the nucleus. In the nucleus, reduction of Cys62 in the p50 subunit of NF-κB is necessary for binding of the transcription factor to its target site in the DNA. In the nucleus, Trx1, Grx1, and Nrx (not shown) have been reported to promote NF-κB binding to the κB site in the DNA. NF-κB, nuclear factor kappa B; Nrx, nucleoredoxin; Txnip, trx interacting protein.