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HECTD3 mediates TRAF3 polyubiquitination and type I interferon induction during bacterial infection
Fubing Li, … , Ceshi Chen, Xiaopeng Qi
Fubing Li, … , Ceshi Chen, Xiaopeng Qi
Published June 19, 2018
Citation Information: J Clin Invest. 2018;128(9):4148-4162. https://doi.org/10.1172/JCI120406.
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Research Article Immunology Infectious disease

HECTD3 mediates TRAF3 polyubiquitination and type I interferon induction during bacterial infection

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Abstract

Lysine-63–linked (K63-linked) polyubiquitination of TRAF3 coordinates the engagement of pattern-recognition receptors with recruited adaptor proteins and downstream activator TBK1 in pathways that induce type I IFN. Whether autoubiquitination or other E3 ligases mediate K63-linked TRAF3 polyubiquitination remains unclear. We demonstrated that mice deficient in the E3 ligase gene Hectd3 remarkably increased host defense against infection by intracellular bacteria Francisella novicida, Mycobacterium, and Listeria by limiting bacterial dissemination. In the absence of HECTD3, type I IFN response was impaired during bacterial infection both in vivo and in vitro. HECTD3 regulated type I IFN production by mediating K63-linked polyubiquitination of TRAF3 at residue K138. The catalytic domain of HECTD3 regulated TRAF3 K63 polyubiquitination, which enabled TRAF3-TBK1 complex formation. Our study offers insights into mechanisms of TRAF3 modulation and provides potential therapeutic targets against infections by intracellular bacteria and inflammatory diseases.

Authors

Fubing Li, Yang Li, Huichun Liang, Tao Xu, Yanjie Kong, Maobo Huang, Ji Xiao, Xi Chen, Houjun Xia, Yingying Wu, Zhongmei Zhou, Xiaomin Guo, Chunmiao Hu, Chuanyu Yang, Xu Cheng, Ceshi Chen, Xiaopeng Qi

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Figure 4

Type I IFN production is impaired in the absence of HECTD3 response to F. novicida.

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Type I IFN production is impaired in the absence of HECTD3 response to F...
(A) RNA-seq analysis of the expression of genes in uninfected and F. novicida–infected WT and Hectd3–/– BMDMs for 8 and 12 hours, respectively. Heatmap showing the expression of genes responsive to type I IFN in uninfected and F. novicida–infected WT and Hectd3–/– BMDMs. (B) BMDMs from WT and Hectd3–/– mice were infected with F. novicida (100 MOI) for indicated times, and expression of Ifnb, Cxcl9, Mx1, and Tnfa was analyzed by qRT-PCR. (C) Production of IFN-β, IL-6, TNF-α, and IL-1β in uninfected (Med) and F. novicida–infected WT and Hectd3–/– BMDMs for 14 hours. (D) Immunoblot analysis of phosphorylation of TBK1, IRF3, STAT3, STAT1, IκBα, ERK, P38, IKKα, and JNK in uninfected and F. novicida–infected WT and Hectd3–/– BMDMs at indicated times. Data represent 3 independent experiments (B–D) and are presented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.
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