TNIP1 in Autoimmune Diseases: Regulation of Toll-like Receptor Signaling

Figure 1

Toll-like receptor signaling—regulation by TNIP1. (a) With TLR dimerization and recruitment of adaptor proteins at the membrane level, ubiquitination of target proteins promotes activation of kinase activity and complex formation. Diverse consequences occur depending on the TLR activated. In the case of TLR3-TRAF3-TRIF, TBK1 becomes ubiquitinated and, in combination with IKKε, promotes phosphorylation of transcription factors (IRF3) upstream of interferon secretion. TLR3 activation may also promote RIP1 ubiquitination, which allows for RIP1 to interact with TAK1/TAB2/3 or NEMO, resulting in gene transcription events regulating inflammation and apoptosis. IRAK1 becomes ubiquitinated followed by TAK1 activation with TAB2/3 binding K-63 linked ubiquitin which forms a hybrid complex with linear (Met1-linked) ubiquitin on NEMO allowing for TAK1 to phosphorylate IKKβ. This eventually results in the release of NF-κB subunits from IκBα. TNIP1 regulation of these events is believed to occur by (b) removal of K63-linked ubiquitin chains via TNIP1/A20 binding and A20 de-ubiquitinase activity and/or (c) inhibition of complex formation by competition for polyubiquitin binding.

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