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

Abstract

TNIP1 protein is increasingly being recognized as a key repressor of inflammatory signaling and a potential factor in multiple autoimmune diseases. In addition to earlier foundational reports of TNIP1 SNPs in human autoimmune diseases and TNIP1 protein-protein interaction with receptor regulating proteins, more recent studies have identified new potential interaction partners and signaling pathways likely modulated by TNIP1. Subdomains within the TNIP1 protein as well as how they interact with ubiquitin have not only been mapped but inflammatory cell- and tissue-specific consequences subsequent to their defective function are being recognized and related to human disease states such as lupus, scleroderma, and psoriasis. In this review, we emphasize receptor signaling complexes and regulation of cytoplasmic signaling steps downstream of TLR given their association with some of the same autoimmune diseases where TNIP1 has been implicated. TNIP1 dysfunction or deficiency may predispose healthy cells to the inflammatory response to otherwise innocuous TLR ligand exposure. The recognition of the anti-inflammatory roles of TNIP1 and improved integrated understanding of its physical and functional association with other signaling pathway proteins may position TNIP1 as a candidate target for the design and/or testing of next-generation anti-inflammatory therapeutics.

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.

Figure 2

IL-23/Th17 axis of psoriasis. Proposed paracrine signaling with TNIP1 regulation in psoriasis where nonimmune cells are keratinocytes [111]. We would suggest that variations of this could be relevant for SLE and SSc, where the nonimmune cells are a podocyte or fibroblast, respectively. For instance, following TLR7 or 9 activation of APCs in SLE, paracrine signaling would include type I interferons.