TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7–9
| Autor: | Vitaly Sedlyarov, Leonhard X. Heinz, Felix Kartnig, Charles E. Whitehurst, Adrijana Stefanovic, André C. Müller, Jun Li, Giulio Superti-Furga, Johannes W. Bigenzahn, Ariel Bensimon, F. James King, Patrick Essletzbichler, Manuele Rebsamen, Mattia D. Pizzagalli, M. Lamine Mbow, Konstantinos Papakostas, Ulrich Goldmann, JangEun Lee, Enrico Girardi, Stefania Scorzoni, Adrián César-Razquin, Utkarsh Kapoor |
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| Jazyk: | angličtina |
| Předmět: |
Male
0301 basic medicine Amino Acid Motifs Nerve Tissue Proteins Plasma protein binding Biology Article 03 medical and health sciences 0302 clinical medicine Solute carriers IRF5 Animals Humans Lupus Erythematosus Systemic Transcription factor Multidisciplinary Innate immune system autoimmunity Intracellular Signaling Peptides and Proteins Membrane Transport Proteins TLR7 TLR8 CXorf21 Endolysosome Immunity Innate 3. Good health Cell biology Toll-like receptors 030104 developmental biology Toll-Like Receptor 7 Toll-Like Receptor 8 Toll-Like Receptor 9 Interferon Regulatory Factors Interferon Type I TASL SLC15A4 Female Signal transduction Lysosomes IRF3 Protein Binding Signal Transduction 030215 immunology |
| Zdroj: | Nature |
| ISSN: | 1476-4687 0028-0836 |
| DOI: | 10.1038/s41586-020-2282-0 |
| Popis: | Toll-like receptors (TLRs) have a crucial role in the recognition of pathogens and initiation of immune responses1-3. Here we show that a previously uncharacterized protein encoded by CXorf21-a gene that is associated with systemic lupus erythematosus4,5-interacts with the endolysosomal transporter SLC15A4, an essential but poorly understood component of the endolysosomal TLR machinery also linked to autoimmune disease4,6-9. Loss of this type-I-interferon-inducible protein, which we refer to as 'TLR adaptor interacting with SLC15A4 on the lysosome' (TASL), abrogated responses to endolysosomal TLR agonists in both primary and transformed human immune cells. Deletion of SLC15A4 or TASL specifically impaired the activation of the IRF pathway without affecting NF-κB and MAPK signalling, which indicates that ligand recognition and TLR engagement in the endolysosome occurred normally. Extensive mutagenesis of TASL demonstrated that its localization and function relies on the interaction with SLC15A4. TASL contains a conserved pLxIS motif (in which p denotes a hydrophilic residue and x denotes any residue) that mediates the recruitment and activation of IRF5. This finding shows that TASL is an innate immune adaptor for TLR7, TLR8 and TLR9 signalling, revealing a clear mechanistic analogy with the IRF3 adaptors STING, MAVS and TRIF10,11. The identification of TASL as the component that links endolysosomal TLRs to the IRF5 transcription factor via SLC15A4 provides a mechanistic explanation for the involvement of these proteins in systemic lupus erythematosus12-14. |
| Databáze: | OpenAIRE |
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