| Autor: |
Tawaratsumida K; Laboratory of Innate Immunity and Signal Transduction, Department of Pathology, Division of Microbiology and Immunology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA., Redecke V; Laboratory of Innate Immunity and Signal Transduction, Department of Pathology, Division of Microbiology and Immunology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA., Wu R; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Kuriakose J; Children's GMP, LLC., St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Bouchard JJ; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Mittag T; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Lohman BK; Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA., Mishra A; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., High AA; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Häcker H; Laboratory of Innate Immunity and Signal Transduction, Department of Pathology, Division of Microbiology and Immunology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA. |
| Abstrakt: |
Toll-like receptors (TLRs) recognize pathogen- and host-derived factors and control immune responses via the adaptor protein MyD88 and members of the interferon regulatory transcription factor (IRF) family. IRFs orchestrate key effector functions, including cytokine release, cell differentiation, and, under certain circumstances, inflammation pathology. Here, we show that IRF activity is generically controlled by the Src kinase family member LYN, which phosphorylates all TLR-induced IRFs at a conserved tyrosine residue, resulting in K48-linked polyubiquitination and proteasomal degradation of IRFs. We further show that LYN activity is controlled by the upstream kinase C-terminal Src kinase (CSK), whose activity, in turn, is controlled by the adaptor protein SPOP, which serves as molecular bridge to recruit CSK into the TLR signaling complex and to activate CSK catalytic activity. Consistently, deletion of SPOP or CSK results in increased LYN activity, LYN-directed IRF degradation, and inhibition of IRF transcriptional activity. Together, the data reveal a key regulatory mechanism for IRF family members controlling TLR biology. |
