A phospho-tyrosine–based signaling module using SPOP, CSK, and LYN controls TLR-induced IRF activity

Author:

Tawaratsumida Kazuki1ORCID,Redecke Vanessa1ORCID,Wu Ruiqiong2ORCID,Kuriakose Jeeba3,Bouchard Jill J.4,Mittag Tanja4ORCID,Lohman Brian K.5,Mishra Ashutosh6ORCID,High Anthony A.6ORCID,Häcker Hans1ORCID

Affiliation:

1. 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.

2. Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.

3. Children’s GMP, LLC., St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.

4. Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.

5. Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.

6. Center for Proteomics and Metabolomics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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