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.