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.
From the State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, Tsinghua University, Beijing 100084, China, National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Shigao
S
Yang
From the State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, Tsinghua University, Beijing 100084, China, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Yinyin
Y
Wang
Center for Structural Biology, School of Life Sciences, Ministry of Education Key Laboratory of Protein Science, Tsinghua University, Beijing 100084, China.
Kunrong
K
Mei
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union medical college, Beijing, 100050, China, and.
Sen
S
Zhang
From the State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, Tsinghua University, Beijing 100084, China, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Xiaojun
X
Sun
From the State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, Tsinghua University, Beijing 100084, China, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Fangli
F
Ren
From the State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, Tsinghua University, Beijing 100084, China, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Sihan
S
Liu
From the State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, Tsinghua University, Beijing 100084, China, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Zi
Z
Yang
Center for Structural Biology, School of Life Sciences, Ministry of Education Key Laboratory of Protein Science, Tsinghua University, Beijing 100084, China.
Xinquan
X
Wang
Key Laboratory of Protein and Peptide Pharmaceuticals, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Zhihai
Z
Qin
From the State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, Tsinghua University, Beijing 100084, China, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China, zhijiec@tsinghua.edu.cn.
Zhijie
Z
Chang
D000818:Animals; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D007686:Kidney Tubules, Distal / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009393:Nephritis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D055503:Protein Multimerization; D051381:Rats; D053722:Receptors, Interleukin-17 / Q000737:chemistry / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics
D016328:NF-kappa B; D053722:Receptors, Interleukin-17; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II
IL-17RD/Sef; NF-κ B (NF-KB); Receptor Regulation; Signal Transduction; TNF Receptor-associated Factor (TRAF); TNFR2; Tumor Necrosis Factor (TNF)