TAOK1 negatively regulates IL-17-mediated signaling and inflammation

Abstract

Interleukin 17 (IL-17) is an important cytokine that can induce tissue inflammation and is involved in the pathogenesis of numerous autoimmune diseases. However, the regulation of its signaling transduction has not been well described. In this study, we report that thousand and one kinase 1 (TAOK1) functions as a negative regulator of IL-17-mediated signal transduction and inflammation. TAOK1 knockdown promotes IL-17-induced cytokine and chemokine expression and the activation of mitogen-activated protein kinases and nuclear factor-κB. We further demonstrate that TAOK1 interacts with IL-17 receptor A (IL-17RA) independent of its kinase activity, and TAOK1 dose-dependently prevents the formation of the IL-17R-Act1 (nuclear factor activator 1, also known as tumor necrosis factor receptor-associated factor 3 interacting protein 2) complex. Consistent with this, TAOK1 deficiency exacerbates colitis in the 2,4,6-trinitrobenzenesulfonic acid)-induced experimental model of inflammatory bowel disease, likely by its promotion of the IL-17-mediated signaling pathway. TAOK1 expression is decreased in the colons of ulcerative colitis patients. In conclusion, these findings suggest that TAOK1 is involved in the development of IL-17-related autoimmune disorders.

Mitochondrial Protein PINK1 Positively Regulates RLR Signaling

“…cDNA was generated from total RNA using reverse transcriptase (Takara). SYBR RT-PCR kits (Takara) were used for quantitative real-time PCR analysis as described (20). The primers used for mRNA analysis are listed in Table 1.…”

The Diverse Roles of TAO Kinases in Health and Diseases

“…TAOKs are implicated in the regulation of inflammation and immunity. Zhang et al [ 44 ] showed that TAOK1 is a negative regulator of interleukin-17 (IL-17)-mediated signal transduction via preventing the formation of the IL-17 receptor and Act1 (nuclear factor activator 1) complex, thus inhibiting IL-17-associated inflammation and potentially modulating autoimmune progression. TAOK1 was also found to increase the lipopolysaccharide (LPS)-induced production of pro-inflammatory cytokines, including IL-6, TNF-α (tumor necrosis factor-α), and IL12p40, in macrophages [ 45 ].…”

Identification of a dual TAOK1 and MAP4K5 inhibitor using a structure-based virtual screening approach

“…TAOK1 can promote structural changes to a cell by activating the MAPK cascade 19 . Both MAP4K5 and TAOK1 are involved with the MAPK signalling, which is a complex signalling cascade linked to organ development and tissue homeostasis 22,23 .…”