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

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

doi:10.1172/JCI120406

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

J Clin Invest. 2018 Aug 31;128(9):4148-4162. doi: 10.1172/JCI120406. Epub 2018 Jul 30.

Authors

Fubing Li¹, Yang Li^{1

2}, Huichun Liang¹, Tao Xu^{1

2}, Yanjie Kong¹, Maobo Huang¹, Ji Xiao³, Xi Chen¹, Houjun Xia¹, Yingying Wu¹, Zhongmei Zhou¹, Xiaomin Guo^{1

2}, Chunmiao Hu^{1

2}, Chuanyu Yang¹, Xu Cheng⁴, Ceshi Chen¹, Xiaopeng Qi^{1

2}

Affiliations

¹ Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, and.
² Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute 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 of Guangzhou Medical University, Guangzhou, China.
⁴ Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.

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.

Keywords: Immunology; Infectious disease; Innate immunity; Ubiquitin-proteosome system.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bacterial Infections / immunology*
Bacterial Infections / metabolism*
Disease Models, Animal
Escherichia coli Infections / immunology
Escherichia coli Infections / metabolism
Female
Francisella
Gram-Negative Bacterial Infections / immunology
Gram-Negative Bacterial Infections / metabolism
Host Microbial Interactions / immunology
Humans
Interferon Type I / biosynthesis*
Listeriosis / immunology
Listeriosis / metabolism
Male
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
TNF Receptor-Associated Factor 3 / chemistry
TNF Receptor-Associated Factor 3 / metabolism*
Ubiquitin-Protein Ligases / deficiency
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*
Ubiquitination

Substances

Interferon Type I
TNF Receptor-Associated Factor 3
HECTd3 protein, mouse
Ubiquitin-Protein Ligases

Grants and funding

Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12010303), 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).