TLR3-mediated IFN-β gene induction is negatively regulated by the TLR adaptor MyD88 adaptor-like.
There is limited insight into the mechanisms involved in the counterregulation of TLR. Given the important role of TLR3/TIR domain-containing adaptor-inducing IFN-β (TRIF)-dependent signalling in innate immunity, novel insights into its modulation is of significance in the context of many physiological and pathological processes. Herein, we sought to perform analysis to definitively assign a mechanistic role for MyD88 adaptor-like (Mal), an activator of TLR2/4 signalling, in the negative regulation of TLR3/TRIF signalling. Biochemical and functional analysis demonstrates that Mal negatively regulates TLR3, but not TLR4, mediated IFN-β production. Co-immunoprecipitation experiments demonstrate that Mal associates with IRF7 (IRF, IFN regulatory factor), not IRF3, and Mal specifically blocks IRF7 activation. In doing so, Mal impedes TLR3 ligand-induced IFN-β induction. Interestingly, Mal does not affect the induction of IL-6 and TNF-α upon TLR3 ligand engagement. Together, these data show that the TLR adaptor Mal interacts with IRF7 and, in doing so, impairs IFN-β induction through the positive regulatory domains I-III enhancer element of the IFN-β gene following poly(I:C) stimulation. Our findings offer a new mechanistic insight into TLR3/TRIF signalling through a hitherto unknown mechanism whereby Mal inhibits poly(I:C)-induced IRF7 activation and concomitant IFN-β production. Thus, Mal is essential in restricting TLR3 signalling thereby protecting the host from unwanted immunopathologies associated with excessive IFN-β production.
Institute of Immunology, Department of Biology, National University of Ireland Maynooth, Maynooth, Co. Kildare, Kildare, Ireland.
Jakub
J
Siednienko
Annett
A
Halle
Kamalpreet
K
Nagpal
Douglas T
DT
Golenbock
Sinéad M
SM
Miggin
D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology / Q000378:metabolism; D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology; D007369:Interferon Inducers / Q000494:pharmacology; D050839:Interferon Regulatory Factor-7 / Q000276:immunology / Q000378:metabolism; D016899:Interferon-beta / Q000276:immunology* / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009185:Myelin Proteins / Q000276:immunology / Q000378:metabolism; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology* / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D011510:Proteolipids / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000276:immunology* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D033942:Adaptor Proteins, Vesicular Transport; D007369:Interferon Inducers; D050839:Interferon Regulatory Factor-7; D016899:Interferon-beta; D015850:Interleukin-6; D026901:Membrane Transport Proteins; D009185:Myelin Proteins; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D053594:Myeloid Differentiation Factor 88; D011070:Poly I-C; D011510:Proteolipids; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C508600:IL6 protein, human; C494234:IRF7 protein, human; C494235:Irf7 protein, mouse; C569026:MAL protein, human; C507779:MYD88 protein, human; C569027:Mal protein, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C470409:TICAM1 protein, human; C495342:TLR2 protein, human; C495344:TLR3 protein, human; C519703:TLR3 protein, mouse; C495345:TLR4 protein, human; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse