title: TRIM38 Negatively Regulates TLR3/4-Mediated Innate Immune and Inflammatory Responses by Two Sequential and Distinct Mechanisms.
abstract: Tripartite motif (TRIM)38 is an E3 ubiquitin ligase that was reported to regulate signaling in innate immune and inflammatory responses in certain cell lines. In this study, we show that Trim38 deficiency markedly increased TLR3- and TLR4-mediated induction of type I IFNs and proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6, in immune cells and in vivo. Trim38 deficiency also caused the mice to be more susceptible to death triggered by polyinosinic-polycytidylic acid, LPS, and Salmonella typhimurium. Mechanistically, TRIM38 catalyzed K48-linked polyubiquitination of the TLR3/4 adapter protein TIR domain-containing adapter-inducing IFN-β at K228 and promoted its proteasomal degradation in immune cells. Moreover, Trim38 was highly induced by type I IFNs, which then negatively regulated TNF-α/IL-1β signaling in IFN-β-primed immune cells, but not unprimed immune cells, by mediating degradation of Tab2 in a lysosomal-dependent process. These results suggest that Trim38 negatively regulates TLR3/4-mediated innate immune and inflammatory responses by two sequential and distinct mechanisms. This study increases our understanding of how the innate immune response is initiated during the early phase of infection to defend against microbial invasion and is efficiently terminated during the late phase to prevent excessive and harmful inflammatory responses.
authors.affiliation: College of Life Sciences, Medical Research Institute, Collaborative Innovation Center for Viral Immunology, Wuhan University, Wuhan 430072, China.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Hu
authors.affiliation: College of Life Sciences, Medical Research Institute, Collaborative Innovation Center for Viral Immunology, Wuhan University, Wuhan 430072, China.
authors.forename: Xue-Qin
authors.initials: XQ
authors.lastname: Xie
authors.affiliation: College of Life Sciences, Medical Research Institute, Collaborative Innovation Center for Viral Immunology, Wuhan University, Wuhan 430072, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
authors.affiliation: College of Life Sciences, Medical Research Institute, Collaborative Innovation Center for Viral Immunology, Wuhan University, Wuhan 430072, China.
authors.forename: Chen-Yang
authors.initials: CY
authors.lastname: Liao
authors.affiliation: College of Life Sciences, Medical Research Institute, Collaborative Innovation Center for Viral Immunology, Wuhan University, Wuhan 430072, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Ye
authors.affiliation: College of Life Sciences, Medical Research Institute, Collaborative Innovation Center for Viral Immunology, Wuhan University, Wuhan 430072, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Lin
authors.affiliation: College of Life Sciences, Medical Research Institute, Collaborative Innovation Center for Viral Immunology, Wuhan University, Wuhan 430072, China shuh@whu.edu.cn.
authors.forename: Hong-Bing
authors.initials: HB
authors.lastname: Shu
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D015151:Immunoblotting; D018836:Inflammation Mediators / Q000276:immunology* / Q000378:metabolism; D016899:Interferon-beta / Q000276:immunology / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008297:Male; D018345:Mice, Knockout; D011070:Poly I-C / Q000276:immunology / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012486:Salmonella typhimurium / Q000276:immunology / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000276:immunology* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology* / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta; C574194:TRIM38 protein, mouse; D044767:Ubiquitin-Protein Ligases; D011070:Poly I-C