Neddylation is required for herpes simplex virus type I (HSV-1)-induced early phase interferon-beta production.
Type I interferons such as interferon-beta (IFN-β) play essential roles in the host innate immune response to herpes simplex virus type I (HSV-1) infection. The transcription of type I interferon genes is controlled by nuclear factor-κB (NF-κB) and interferon regulatory factor (IRF) family members including IRF3. NF-κB activation depends on the phosphorylation of inhibitor of κB (IκB), which triggers its ubiqitination and degradation. It has been reported that neddylation inhibition by a pharmacological agent MLN4924 potently suppresses lipopolysaccharide (LPS)-induced proinflammatory cytokine production with the accumulation of phosphorylated IκBα. However, the role of neddylation in type I interferon expression remains unknown. Here, we report that neddylation inhibition with MLN4924 or upon UBA3 deficiency led to accumulation of phosphorylated IκBα, impaired IκBα degradation, and impaired NF-κB nuclear translocation in the early phase of HSV-1 infection even though phosphorylation and nuclear translocation of IRF3 were not affected. The blockade of NF-κB nuclear translocation by neddylation inhibition becomes less efficient at the later time points of HSV-1 infection. Consequently, HSV-1-induced early phase IFN-β production significantly decreased upon MLN4924 treatment and UBA3 deficiency. NF-κB inhibitor JSH-23 mimicked the effects of neddylation inhibition in the early phase of HSV-1 infection. Moreover, the effects of neddylation inhibition on HSV-1-induced early phase IFN-β production diminished in the presence of NF-κB inhibitor JSH-23. Thus, neddylation contributes to HSV-1-induced early phase IFN-β production through, at least partially, promoting NF-κB activation.
Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, P. R. China.
Xueying
X
Zhang
Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, P. R. China.|Laboratory of Snake Venom, Fujian Medical University, 88 Jiaotong Road, Fuzhou 350004, P. R. China.
Zhenjie
Z
Ye
Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, P. R. China.
Yujun
Y
Pei
Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, P. R. China.
Guihua
G
Qiu
Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, P. R. China.
Qingyang
Q
Wang
Laboratory of Snake Venom, Fujian Medical University, 88 Jiaotong Road, Fuzhou 350004, P. R. China.
Yunlu
Y
Xu
Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, P. R. China.
Beifen
B
Shen
Department of Molecular Immunology, Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, P. R. China.
Jiyan
J
Zhang
D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003517:Cyclopentanes / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D006561:Herpes Simplex / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D016899:Interferon-beta / Q000096:biosynthesis* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D010655:Phenylenediamines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D014452:Ubiquitins / Q000378:metabolism
C549066:4-methyl-N1-(3-phenylpropyl)benzene-1,2-diamine; D003517:Cyclopentanes; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D016328:NF-kappa B; D010655:Phenylenediamines; D011743:Pyrimidines; C491805:Ube1c protein, mouse; D014452:Ubiquitins; D016899:Interferon-beta; D003546:Cysteine Endopeptidases; C539933:pevonedistat