IFIT5 positively regulates NF-κB signaling through synergizing the recruitment of IκB kinase (IKK) to TGF-β-activated kinase 1 (TAK1).
Precise regulation of NF-κB signaling pathways is essential to effective host immune response. However, the specific molecular mechanism underlying NF-κB activation by different stimuli is not fully understood. Here we demonstrate that IFIT5, one of the interferon induced tetratricopeptide repeat family members, enhances IKK phosphorylation and NF-κB activation through interacting with TAK1 and IKK. Following TNF-α treatment, IFIT5 interacted with TAK1 or IKK complex and synergized the recruitment of IKK to TAK1 in a dose dependent manner. Consistent with these observations, knockdown of IFIT5 decreased the recruitment of IKK to TAK1 and markedly weakened IKK phosphorylation, further reducing the production of NF-κB target genes IL-8 and ICAM-1. Moreover, we found that IFIT5 also promoted SeV-induced IKK phosphorylation and NF-κB activation by regulating the recruitment of IKK to TAK1. Our findings identify a previously unrecognized role of IFIT5 as a positive regulator in IKK phosphorylation and NF-κB activation, highlighting that IFIT5 serves as an important mediator in innate immunity.
Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
Caishang
C
Zheng
Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
Zhenhua
Z
Zheng
State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Science, Wuhan 430071, China.
Zhenfeng
Z
Zhang
State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Science, Wuhan 430071, China.
Jin
J
Meng
Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
Yan
Y
Liu
Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
Xianliang
X
Ke
State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Science, Wuhan 430071, China.
Qinxue
Q
Hu
Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China. Electronic address: wanghz@wh.iov.cn.
Hanzhong
H
Wang
D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D016209:Interleukin-8 / Q000096:biosynthesis; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D015398:Signal Transduction; D000099151:MAP Kinase Kinase Kinase 7
D051550:I-kappa B Kinase; D016209:Interleukin-8; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D009363:Neoplasm Proteins; D000099151:MAP Kinase Kinase Kinase 7; C110985:IFIT5 protein, human
IFIT5; IKK; Innate immunity; NF-κB; Phosphorylation; TAK1