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

• Published in: The Journal of biological chemistry 2015-01, Vol.290 (2), p.861-871
• Main Authors: Yang, Shigao, Wang, Yinyin, Mei, Kunrong, Zhang, Sen, Sun, Xiaojun, Ren, Fangli, Liu, Sihan, Yang, Zi, Wang, Xinquan, Qin, Zhihai, Chang, Zhijie
• Format: Article
• Language: English
• Subjects: Animals; Cell Biology; Epithelial Cells - metabolism; Epithelial Cells - pathology; Humans; IL-17RD/Sef; Inflammation - etiology; Inflammation - metabolism; Inflammation - pathology; Kidney Tubules, Distal - metabolism; Kidney Tubules, Distal - pathology; Nephritis - etiology; Nephritis - metabolism; Nephritis - pathology; NF-kappa B - genetics; NF-kappa B - metabolism; NF-κ B (NF-KB); Protein Multimerization; Rats; Receptor Regulation; Receptors, Interleukin-17 - chemistry; Receptors, Interleukin-17 - metabolism; Receptors, Tumor Necrosis Factor, Type I - genetics; Receptors, Tumor Necrosis Factor, Type I - metabolism; Receptors, Tumor Necrosis Factor, Type II - chemistry; Receptors, Tumor Necrosis Factor, Type II - metabolism; Signal Transduction; Signal Transduction - genetics; TNF Receptor-associated Factor (TRAF); TNFR2; Transcriptional Activation - genetics; Tumor Necrosis Factor (TNF)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.586560

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.TNFR1 signaling has been intensively studied, but it remains unclear how TNFR2 transduces TNF-α signal under inflammatory conditions. TNFR2 associates with IL-17RD, resulting in receptor aggregation and TRAF2 recruitment, leading to promotion of NF-κB signaling in renal tubular epithelial cells. TNFR2 cooperates with IL-17RD to activate NF-κB. The TNFR2·IL-17RD heteromer might be implicated in nephritis.