Nature Immunology 7, 148 - 155 (2006)
Published online: 15 January 2006; | doi:10.1038/ni1299
Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradationAshley Mansell1, Rosealee Smith1, Sarah L Doyle2, Pearl Gray2, Jennifer E Fenner1, Peter J Crack1, Sandra E Nicholson3, Douglas J Hilton3, Luke A J O'Neill2, 4
& Paul J Hertzog1, 41
Centre for Functional Genomics and Human Disease, Monash Institute of Medical Research, Monash University, Melbourne, Victoria, Australia. 2
School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland. 3
Walter and Eliza Hall Institute, Parkville, Victoria, Australia. 4
These authors contributed equally to this work.
Correspondence should be addressed to Paul J Hertzog paul.hertzog@med.monash.edu.au Toll-like receptor (TLR) signals that initiate innate immune responses to pathogens must be tightly regulated to prevent excessive inflammatory damage to the host. The adaptor protein Mal is specifically involved in signaling via TLR2 and TLR4. We demonstrate here that after TLR2 and TLR4 stimulation Mal becomes phosphorylated by Bruton's tyrosine kinase (Btk) and then interacts with SOCS-1, which results in Mal polyubiquitination and subsequent degradation. Removal of SOCS-1 regulation potentiates Mal-dependent p65 phosphorylation and transactivation of NF- B, leading to amplified inflammatory responses. These data identify a target of SOCS-1 that regulates TLR signaling via a mechanism distinct from an autocrine cytokine response. The transient activation of Mal and subsequent SOCS-1–mediated degradation is a rapid and selective means of limiting primary innate immune response.
MORE ARTICLES LIKE THIS These links to content published by NPG are automatically generated.
|
