机构：[1]Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province,[2]Key Laboratory of Bioactive Peptides of Yunnan Province, KunmingInstitute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China[3]State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital ofGuangzhou Medical University, Guangzhou, China[4]Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
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.
基金：
We thank C. Gao (Shandong University School of Basic Medical
Sciences, Jinan, China), H.B. Shu (Wuhan University, Wuhan,
China), and H. Xiao (Institut Pasteur of Shanghai, Chinese Academy
of Sciences, Shanghai, China) for TBK1, STING, and TRIF
plasmids; Y. Qian (Institute of Health Sciences, Shanghai Institutes
for Biological Sciences, Shanghai, China) for Traf3–/– MEFs;X. Zhang (Institut Pasteur of Shanghai) for GFP-expressing M.
bovis BCG and regular BCG strains; J. Zhou (Kunming Institute
of Zoology) for HSV-1; and S.Z. Duan (Institute for Nutritional
Sciences, Shanghai Institutes for Biological Sciences)
for L929 cells. This work was supported by grants from
National Key Research and Development Program of China
(2017YFD0500300), the Strategic Priority Research Program
of the Chinese Academy of Sciences (XDA12010303), the
National Natural Science Foundation of China (81325016,U1602221, 31771516, 81701578, 31701134, 81402206, 81773149,
and 81672639), and the Chinese Academy of Sciences (CXJJ-
17-M141, Y4ZK111B01, and Y602381081).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2018]版：
大类|1 区医学
小类|1 区医学：研究与实验
最新[2023]版：
大类|1 区医学
小类|1 区医学：研究与实验
第一作者：
第一作者机构：[1]Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province,
通讯作者：
通讯机构：[1]Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province,[2]Key Laboratory of Bioactive Peptides of Yunnan Province, KunmingInstitute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China[*1]Kunming Institute of Zoology, Chinese Academy of Sciences, 32 East Jiaochang Road, Kunming, Yunnan 650223, China
推荐引用方式(GB/T 7714)：
Li Fubing,Li Yang,Liang Huichun,et al.HECTD3 mediates TRAF3 polyubiquitination and type I interferon induction during bacterial infection.[J].The Journal of clinical investigation.2018,128(9):4148-4162.doi:10.1172/JCI120406.
APA：
Li Fubing,Li Yang,Liang Huichun,Xu Tao,Kong Yanjie...&Qi Xiaopeng.(2018).HECTD3 mediates TRAF3 polyubiquitination and type I interferon induction during bacterial infection..The Journal of clinical investigation,128,(9)
MLA：
Li Fubing,et al."HECTD3 mediates TRAF3 polyubiquitination and type I interferon induction during bacterial infection.".The Journal of clinical investigation 128..9(2018):4148-4162
医学