Abstract
Recent genome-wide association studies have implicated the tumor necrosis factor receptor-associated factor 3-interacting protein 2 (TRAF3IP2) gene and its product, nuclear factor-kappa-B activator 1 (Act1), in the development of psoriatic arthritis (PsA). The high level of sequence homology of the TRAF3IP2 (Act1) gene across the animal kingdom and the presence of the Act1 protein in multiple cell types strongly suggest that the protein is of importance in normal cellular function. Act1 is an adaptor protein for the interleukin-17 (IL-17) receptor, and recent observations have highlighted the significance of IL-17 signaling and localized inflammation in autoimmune diseases. This review summarizes data from recent genome-wide association studies as well as immunological and molecular investigations of Act1. Together, these studies provide new insight into the role of IL-17 signaling in PsA. It is well established that IL-17 activation of tumor necrosis factor receptor-associated factor 6 (TRAF6) signaling pathways normally leads to nuclear factor-kappa-B-mediated inflammation. However, the dominant PsA-associated TRAF3IP2 (Act1) gene single-nucleotide polymorphism (rs33980500) results in decreased binding of Act1 to TRAF6. This key mutation in Act1 could lead to a greater association of the IL-17 receptor with TRAF2/TRAF5 and this in turn suggests an alternative function for IL-17 in PsA. The recent observations described and discussed in this review raise the clinically significant possibility of redefining the immunological role of IL-17 in PsA and provide a basis for defining future studies to elucidate the molecular and cellular functions of Act1.
Highlights
In 2010, a new association between the tumor necrosis factor receptor-associated factor 3-interacting protein 2 (TRAF3IP2) gene and the immune-mediated diseases psoriatic arthritis (PsA) and psoriatic vulgaris (PsV) was identified by a genome-wide association study (GWAS) [1]
activator 1 (Act1) is the main adaptor protein that has been associated with interleukin-17 receptor (IL-17R), and there is good evidence to suggest that Act1 plays an important role in immune cell signaling
The structure of the Act1 adaptor protein includes a SEFIR domain, a domain found on each of the IL-17Rs and through which Act1 is thought to interact. This suggests a functional connection between Act1 and each of the IL-17Rs
Summary
In 2010, a new association between the tumor necrosis factor receptor-associated factor 3-interacting protein 2 (TRAF3IP2) gene and the immune-mediated diseases psoriatic arthritis (PsA) and psoriatic vulgaris (PsV) was identified by a genome-wide association study (GWAS) [1]. The proteins downstream of TRAF6 which lead to the activation of NF-κB, a master transcription factor responsible for the regulation of pro-inflammatory gene expression, have been identified in both the IL-17R [31,32] and TLR [33] signaling pathways. The inhibition of IKKε, which modifies Act to increase TRAF2/5 binding, causes a decrease in the production of pro-inflammatory cytokines/chemokines associated with the synergy between IL-17 and TNF [6]. In the TNF signaling pathway, TRAF5/6 interacts with a wide variety of proteins (NF-κB-inducing kinase (NIK), MAP kinase/ERK kinase kinase 1 (MEKK1), transforming growth factor, atypical protein kinase C, or factor β-activated kinase), and this interaction phosphorylates the IKK complex, leading to the downstream release of NF-κB. Further study is required in order to obtain a clearer understanding of how the signaling pathways function in epithelial cells, in both controls and those with PsA-associated SNPs
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