Interaction of IFNλR1 with TRAF6 regulates NF-κB activation and IFNλR1 stability.
IFNλR1 is a member of the class II cytokine receptor family, and it associates with IL-10R2 to form a functional receptor complex, IFNλR. This receptor complex transduces signals from IFNλs (IFNλ1, IFNλ2, and IFNλ3), promoting antiviral and antiproliferative activities similar to those of type I IFNs. In an effort to further understand signal transduction through IFNλR1, we used bioinformatics analysis and identified a tumor necrosis factor receptor-associated factor 6 (TRAF6)-binding motif in the intracellular domain of IFNλR1. In subsequent immunoprecipitation and GST pull-down assays, IFNλR1 was shown to immunoprecipitate with TRAF6 and was pulled down by GST-TRAF6. Endogenous IFNλR1 and TRAF-6 interaction implies that these proteins really interact in the cells. This interaction was abrogated upon mutation of the TRAF6-binding motif in IFNλR1. Furthermore, the interaction between IFNλR1 and TRAF6 inhibited TRAF6-induced NF-κB activation, likely due to a reduction in TRAF6 autoubiquitination. Moreover, co-expression of IFNλR1 with TRAF6 significantly increased the stability of IFNλR1, thereby prolonging its half-life and enhancing its steady-state level in cultured cells.
National Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.
Yun-Fei
YF
Xie
Ying-Bin
YB
Cui
Xi-Wu
XW
Hui
Lan
L
Wang
Xiao-Li
XL
Ma
Hong
H
Chen
Xin
X
Wang
Bing-Ren
BR
Huang
D020816:Amino Acid Motifs; D001665:Binding Sites; D019295:Computational Biology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids; D011485:Protein Binding; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D054875:Ubiquitination; D000096743:Interferon gamma Receptor
D016328:NF-kappa B; D017471:Receptors, Interferon; D048029:TNF Receptor-Associated Factor 6; D000096743:Interferon gamma Receptor