A phospho-tyrosine-based signaling module using SPOP, CSK, and LYN controls TLR-induced IRF activity.
A phospho-tyrosine-based signaling module using SPOP, CSK, and LYN controls TLR-induced IRF activity.
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DOI：
10.1126/sciadv.abq0084
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发表时间：
2022-07-08
期刊：
影响因子：
13.6
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中科院分区：
文献类型：
--
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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. TLRs use MyD88, SPOP, CSK, and LYN to control IRF activity via phosphorylation of a conserved tyrosine residue.
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通讯作者：
Lee I
DOI：
10.1073/pnas.0408918102
发表时间：
2005-05-24
影响因子：
11.1
作者：
Hernádez-Muñoz, I;Lund, AH;van Lohuizen, M
通讯作者：
van Lohuizen, M