The human adaptor SARM negatively regulates adaptor protein TRIF -dependent Toll-like receptor signaling

Toll-like receptors discriminate between different pathogen-associated molecules and activate signaling cascades that lead to immune responses. The specificity of Toll-like receptor signaling occurs by means of adaptor proteins containing Toll–interleukin 1 receptor (TIR) domains. Activating functio...

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Bibliographic Details
Published in:Nature Immunology 2006-10, Vol.7 (10), p.1074-1081
Main Authors: Bowie, Andrew G, Carty, Michael, Goodbody, Rory, Schröder, Martina, Stack, Julianne, Moynagh, Paul N
Format: Article
Language:English
Subjects:
Adaptor proteins
Adaptor Proteins, Vesicular Transport - antagonists & inhibitors
Adaptor Proteins, Vesicular Transport - genetics
Adaptor Proteins, Vesicular Transport - metabolism
Armadillo Domain Proteins - antagonists & inhibitors
Armadillo Domain Proteins - genetics
Armadillo Domain Proteins - metabolism
Biomedical and Life Sciences
Biomedicine
Cells, Cultured
Chemokines
Chemokines - genetics
Cytokines - genetics
Cytoskeletal Proteins - antagonists & inhibitors
Cytoskeletal Proteins - genetics
Cytoskeletal Proteins - metabolism
Gene Expression Regulation
Humans
Immune response
Immunology
Infectious Diseases
Interferon Regulatory Factor-7 - antagonists & inhibitors
Interleukin 1
Mammals
MyD88 protein
Myeloid Differentiation Factor 88 - metabolism
NF-kappa B - metabolism
Pathogens
Protein Structure, Tertiary - genetics
RNA Interference
RNA, Small Interfering - pharmacology
Signal Transduction - genetics
Toll-Like Receptor 3 - metabolism
Toll-Like Receptor 4 - metabolism
Toll-like receptors
Toll-Like Receptors - metabolism
Transcriptional Activation
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Summary:Toll-like receptors discriminate between different pathogen-associated molecules and activate signaling cascades that lead to immune responses. The specificity of Toll-like receptor signaling occurs by means of adaptor proteins containing Toll–interleukin 1 receptor (TIR) domains. Activating functions have been assigned to four TIR adaptors: MyD88, Mal, TRIF and TRAM. Here we characterize a fifth TIR adaptor, SARM, as a negative regulator of TRIF-dependent Toll-like receptor signaling. Expression of SARM blocked gene induction 'downstream' of TRIF but not of MyD88. SARM associated with TRIF, and 'knockdown' of endogenous SARM expression by interfering RNA led to enhanced TRIF-dependent cytokine and chemokine induction. Thus, the fifth mammalian TIR adaptor SARM is a negative regulator of Toll-like receptor signaling.
ISSN:1529-2908
1529-2916
1365-2567
DOI:10.1038/ni1382