ArticleScience advances2022
A phospho-tyrosine-based signaling module using SPOP, CSK, and LYN controls TLR-induced IRF activity.
Article in Science advances, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
What it found
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The trial behind it
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Who cites it
12 citing papers in PubMed, 15 citations in OpenAlex.
- Not only as a Cullin3 ligase adaptor, SPOP may also act as a molecular bridge.Genes & diseases · 2027Review
- Lyn expression in macrophages promotes TLR activation and restricts proliferation in an isoform-independent manner.Journal of leukocyte biology · 2025Article
- Lyn restrains lupus via kinase-independent mechanisms that limit Toll-like receptor activation and type I interferon responsiveness.Science advances · 2025Article
- Mechanisms that matter: unbiased cellular screening for degraders.npj drug discovery · 2025Review
- Deep phosphotyrosine characterisation of primary murine T cells using broad spectrum optimisation of selective triggering.Proteomics · 2024Article
- The dualistic role of Lyn tyrosine kinase in immune cell signaling: implications for systemic lupus erythematosus.Frontiers in immunology · 2024Review
- Pellino 3 promotes the colitis-associated colorectal cancer through suppression of IRF4-mediated negative regulation of TLR4 signalling.Molecular oncology · 2023Article
- MiRNA-338-3p Inhibits Neuroinflammation in the Corpus Callosum of LCV-LPS Rats Via STAT1 Signal Pathway.Cellular and molecular neurobiology · 2023Article
- Article
- Editorial: Regulation and dysfunction of CSK and CHK.Frontiers in cell and developmental biology · 2023Article
- Regulation, targets and functions of CSK.Frontiers in cell and developmental biology · 2023Review
- Dissection of the catalytic and regulatory structure-function relationships of Csk protein tyrosine kinase.Frontiers in cell and developmental biology · 2023Review
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.