Review Article
Redox Regulation of Inflammatory Processes Is Enzymatically Controlled
Figure 3
TLR signaling is redox-regulated. The general concept of the TLR signaling is illustrated, emphasizing the redox-regulated steps and molecules; note that this illustration is simplified and that specific TLR pathways include different proteins. PAMPs and DAMPs are recognized by their specific TLR, which can lead to homo- and heterodimerisation. Upon ligand binding, the TLR associates with the adaptor protein Myd88, which is sensitive to oxidation by hydrogen peroxide and can be regulated by Nrx. Myd88 recruits IRAK4 that phosphorylates IRAK1, which in turn activates additional proteins (e.g., TRAFs and IKK, not shown). MAP kinases and NFκB are activated. MAP kinase signaling is regulated by Trx1 and Grx1 and eventually activates the transcription factor AP1, which has two Cys residues in its DNA binding domain that are reduced by Trx1 via Ref1. The NFκB subunits p50 and p60 are kept in an inhibitory iκB/NFκB-complex in the cytosol. Reduced Trx1 inhibits the dissociation of this complex. Upon dissociation, iκB is phosphorylated and degraded by the proteasome. NF-κB translocates into the nucleus, where it binds to the DNA, a process that depends on the reduction of Cys62 and is regulated by Trx1, Grx1, and/or Nrx. An additional redox-regulated pathway involving ASK1 exists in TLR4 signaling. ASK1 is kept in an inactive complex by reduced Trx1. Upon TLR activation, Trx1 is oxidized, the complex dissociates and active ASK1 regulates JNK activity via different proteins including TRAFs.