TRIM8 Negatively Regulates TLR3/4-Mediated Innate Immune Response by Blocking TRIF-TBK1 Interaction

TLR-mediated signaling pathways play critical roles in host defense against microbials. However, dysregulation of innate immune and inflammatory responses triggered by TLRs would result in harmful damage to the host. Using a gene-knockout mouse model, we show that tripartite motif (TRIM) 8 negativel...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2017-09, Vol.199 (5), p.1856-1864
Main Authors: Ye, Wen, Hu, Ming-Ming, Lei, Cao-Qi, Zhou, Qian, Lin, Heng, Sun, Ming-Shun, Shu, Hong-Bing
Format: Article
Language:English
Subjects:
Adaptor Proteins, Vesicular Transport - metabolism
Animals
Body weight
Carrier Proteins - genetics
Carrier Proteins - metabolism
Cytokines - genetics
Cytokines - metabolism
HEK293 Cells
Humans
Immune response
Immunity, Innate
Inflammation
Inflammation - immunology
Inflammation - microbiology
Inflammation Mediators - metabolism
Innate immunity
Interleukin 1
Interleukin 1 receptors
Interleukin 6
Lipopolysaccharides
Lipopolysaccharides - immunology
Mice
Mice, Inbred C57BL
Mice, Knockout
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - metabolism
Poly I-C - immunology
Polyinosinic:polycytidylic acid
Protein Binding
Protein-Serine-Threonine Kinases - metabolism
RANTES
Rodents
Salmonella
Salmonella Infections - immunology
Salmonella typhimurium - immunology
Septic shock
Shock, Septic - immunology
Signal Transduction
TLR3 protein
TLR4 protein
Toll-Like Receptor 3 - metabolism
Toll-Like Receptor 4 - metabolism
Toll-like receptors
Tumor necrosis factor
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Summary:TLR-mediated signaling pathways play critical roles in host defense against microbials. However, dysregulation of innate immune and inflammatory responses triggered by TLRs would result in harmful damage to the host. Using a gene-knockout mouse model, we show that tripartite motif (TRIM) 8 negatively regulates TLR3- and TLR4-mediated innate immune and inflammatory responses. TRIM8 deficiency leads to increased polyinosinic-polycytidylic acid- and LPS-triggered induction of downstream anti-microbial genes including , , , and , evaluated serum cytokine levels, and increased susceptibility of mice to polyinosinic-polycytidylic acid- and LPS-induced inflammatory death as well as infection-induced loss of body weight and septic shock. TRIM8 interacted with Toll/IL-1 receptor domain-containing adapter-inducing IFN-β and mediated its K6- and K33-linked polyubiquitination, leading to disruption of the Toll/IL-1 receptor domain-containing adapter-inducing IFN-β-TANK-binding kinase-1 association. Our findings uncover an additional mechanism on the termination of TLR3/4-mediated inflammatory and innate immune responses.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1601647