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-κB signaling. TNFR2 associates with IL-17RD, leading to mutual receptor aggregation and TRAF2 recruitment, which further activate the downstream cascade of NF-κB signaling. Depletion of IL-17RD impaired TNFR2-mediated activation of NF-κB 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·TNFR2 complex in activation of NF-κB may explain the role of TNFR2 in inflammatory diseases including nephritis.

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