Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation.
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-kappaB, 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.
Mansell
Ashley
A
Centre for Functional Genomics and Human Disease, Monash Institute of Medical Research, Monash University, Melbourne, Victoria, Australia.
Smith
Rosealee
R
Doyle
Sarah L
SL
Gray
Pearl
P
Fenner
Jennifer E
JE
Crack
Peter J
PJ
Nicholson
Sandra E
SE
Hilton
Douglas J
DJ
O'Neill
Luke A J
LA
Hertzog
Paul J
PJ
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D007113:Immunity, Innate; D026901:Membrane Transport Proteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D009185:Myelin Proteins / Q000276:immunology / Q000378:metabolism*; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D010766:Phosphorylation; D011510:Proteolipids / Q000276:immunology / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014443:Tyrosine / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
D002352:Carrier Proteins; C569026:MAL protein, human; C569027:Mal protein, mouse; D026901:Membrane Transport Proteins; D009185:Myelin Proteins; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D011510:Proteolipids; C498144:Rela protein, mouse; D012097:Repressor Proteins; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D051996:Transcription Factor RelA; D025801:Ubiquitin; D014443:Tyrosine