Tumor Necrosis Factor Receptor 2 (TNFR2)•Interleukin-17 Receptor D (IL-17RD) Heteromerization Reveals a Novel Mechanism for NF-κB Activation

TNF receptor 2 (TNFR2) exerts diverse roles in the pathogenesis of inflammatory and autoimmune diseases. Here, we report that TNFR2 but not TNFR1 forms a heteromer with interleukin-17 receptor D (IL-17RD), also named Sef, to activate NF-kappa B signaling. TNFR2 associates with IL-17RD, leading to mutual receptor aggregation and TRAF2 recruitment, which further activate the downstream cascade of NF-kappa B signaling. Depletion of IL-17RD impaired TNFR2-mediated activation of NF-kappa B signaling. Importantly, IL-17RD was markedly increased in renal tubular epithelial cells in nephritis rats, and a strong interaction of TNFR2 and IL-17RD was observed in the renal epithelia. The IL-17RD center dot TNFR2 complex in activation of NF-kappa B may explain the role of TNFR2 in inflammatory diseases including nephritis.