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Review
. 2012 Oct 31;14(5):226.
doi: 10.1186/ar4071.

New insight into the functions of the interleukin-17 receptor adaptor protein Act1 in psoriatic arthritis

Matthew S Doyle, Emily S Collins, Oliver M FitzGerald, Stephen R Pennington
Review

New insight into the functions of the interleukin-17 receptor adaptor protein Act1 in psoriatic arthritis

Matthew S Doyle et al. Arthritis Res Ther. .

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.

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Figures

Figure 1
Figure 1
Structure of the Act1 adaptor protein. Act1 contains two TRAF-binding motifs (residues EESE (35 to 42) and EESE (333 to 337)), a helix-loop-helix (HLH) domain (residues 135 to 190), a SEFIR domain (residues 394 to 574), and a coil-coiled (C-C) domain (residues 470 to 500). The SNPs (SNP1 (D10N or Asp10Asn) = rs33980500 and SNP2 (R74W or Arg74Trp) = rs13190932) and the experimentally determined phosphorylation locations are shown above the Act1 domain structure. Act1, nuclear factor-kappa-B activator 1; SEFIR, similar expression to fibroblast growth factor genes/interleukin-17 receptor; SNP, single-nucleotide polymorphism; TRAF, tumor necrosis factor receptor-associated factor.
Figure 2
Figure 2
The structure (exon/intron) of the TRAF3IP2/Act1 gene and the location of single-nucleotide polymorphisms from the genome-wide association study. The risk alleles are in bold. For each haplotype, odds ratios (ORs) (and 95% confidence intervals) compare the occurrence of the haplotype versus all three other alleles. The single-nucleotide polymorphisms (rs33980500 and rs13190932) occur within the N-terminal region of TRAF3IP2 (Figure 1). Reproduced with permission from Huffmeier and colleagues [1]. Act1, nuclear factor-kappa-B activator 1; TRAF3IP2, tumor necrosis factor receptor-associated factor 3-interacting protein 2.
Figure 3
Figure 3
The IL-17R/Act1/TRAF protein complex. The extracellular IL-17R binds the IL-17 cytokines. Act1 proteins bind to the intra-cellular SEFIR motif, which is present on both of the receptors. The Act1 adaptor proteins contain TRAF motifs, which bind different TRAF proteins. Downstream progression leads to activation of pro-inflammatory genes. Act1, nuclear factor-kappa-B activator 1; IKK, IkB kinase; IL-17, interleukin-17; IL-17R, interleukin-17 receptor; NF-κB, nuclear factor-kappa-B; SEFIR, similar expression to fibroblast growth factor genes/interleukin-17 receptor; TAB, transforming growth factor-beta-activated kinase 1 (TAK1)-binding protein; TAK1, transforming growth factor-beta-activated kinase 1; TRAF, tumor necrosis factor receptor-associated factor.
Figure 4
Figure 4
Comparison of the dual roles of TRAF6 in the TLR and IL-17R signaling pathways. Downstream signaling interactions and post translational modifications of proteins involved in the TLR/IL-17R signaling pathways. TRAF6 is a key signaling protein in inflammation. See 'IL-17 receptor and TLR4 signaling' section of text for details. Act1, nuclear factor-kappa-B activator 1; AP-1, activator protein 1; IKK, IkB kinase; IL-17, interleukin-17; IL-17R, interleukin-17 receptor; IRAK4, interleukin receptor associated kinase 4; IRF5, interferon regulatory factor 5; JNK, c-Jun N-terminal kinases; LPS, lipopolysaccharide; Mal, MyD88 associate ligand; MEKK, MAP kinase/ERK kinase kinase; MyD88, myeloid differentiation primary response gene; NEMO, nuclear factor-kappa-B essential modulator protein; NF-κB, nuclear factor-kappa-B; TAB, transforming growth factor-beta-activated kinase 1 (TAK1)-binding protein; TAK1, transforming growth factor-beta-activated kinase 1; TLR, Toll-like receptor; TRAF6, tumor necrosis factor receptor-associated factor 6.
Figure 5
Figure 5
TRAF6 and TRAF2/5 signaling pathways. (a) The endogenous TRAF6 and TRAF2/5 signaling pathways and post-translational modifications. (b) The presence of the psoriatic arthritis-associated single-nucleotide polymorphism (SNP) (rs33980500) could affect the proteins downstream of Act1. The decrease in TRAF6 binding could result in an increase in the TRAF2/5 signaling pathway and this in turn may lead to increased CXCL1 mRNA and protein expression. Act1, nuclear factor-kappa-B activator 1; ASF, alternative splicing factor; IKK, IkB kinase; IL-17, interleukin-17; IL-17R, interleukin-17 receptor; NF-κB, nuclear factor-kappa-B; TAB, transforming growth factor-beta-activated kinase 1 (TAK1)-binding protein; TAK1, transforming growth factor-beta-activated kinase 1; TRAF6, tumor necrosis factor receptor-associated factor 6.
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