TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7–9
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ABSTRACT:
PROVIDER: PRJNA551037 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11544717.fastq.gz | Fastqsanger.gz | |||
| SRR11544718.fastq.gz | Fastqsanger.gz | |||
| SRR11544719.fastq.gz | Fastqsanger.gz | |||
| SRR11544720.fastq.gz | Fastqsanger.gz | |||
| SRR11544721.fastq.gz | Fastqsanger.gz |
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Project description:Toll-like receptors (TLRs) have a crucial role in the recognition of pathogens and initiation of immune responses. Here we show that a previously uncharacterized protein encoded by CXorf21—a gene that is associated with systemic lupus erythematosus—interacts with the endolysosomal transporter SLC15A4, an essential but poorly understood component of the endolysosomal TLR machinery also linked to autoimmune disease. 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 TRIF. 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 erythematosus.
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Project description: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.
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Project description:Genetic variants in IRF5 are associated with multiple immune-mediated diseases. IRF5 has been predominantly focused on for its regulation of myeloid-derived cells. We found that IRF5 contributes to CD4+ T cell outcomes and that it regulates early T cell receptor-initiated signaling and subsequently translocates to the nucleus where it binds to promoters of various genes regulated with T cell activation. We report the chromatin state of freshly isolated and activated IRF5+/+ and IRF5-/- CD4+ T cells in vitro. While there are minimal differential peaks between freshly isolated IRF5+/+ and IRF5-/- CD4+ T cells, once activated multiple differential peaks are observed between IRF5+/+ and IRF5-/- CD4+ T cells.
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Project description:IRF5 genetic risk variants drive myeloid-specific IRF5 hyper-activation and pre-symptomatic SLE
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Project description:Toll-like receptor 7 (TLR7) plays a key role in the recognition of RNA viruses and the subsequent induction of an innate immune response. TLR7 contains two ligand binding pockets that recognize distinct RNA degradation products: Pocket 1 recognizes guanosine nucleotides and pocket 2 coordinates short, pyrimidine-rich RNA fragments, while the engagement of both pockets is required to activate TLR7. How these ligands are generated within the endolysosomal compartment is currently unknown. Using a pDC cell line, we here show that the endonuclease RNase T2 and the 5' exonucleases PLD3 and PLD4 act in concert to produce these ligands. On the one hand, RNase T2 generates 2',3'-cyclophosphate-guanosine terminated RNA fragments upon which PLD exonuclease activity acts to release the terminal 2',3'-cyclic GMP. This molecule serves as the physiological ligand for the first binding pocket. On the other hand, PLD activity is also required to generate short RNA fragments that occupy the second binding pocket of TLR7. While PLD3 and PLD4 exert comparable catalytic activities, the almost exclusive expression of PLD4 in pDCs suggests that PLD4 is the relevant exonuclease for pDC activation in the human system. Biochemical and structural studies of PLD3 and PLD4 show that these enzymes form homodimers with two ligand binding sites. Dimer formation is critical for catalytic activity, and previously identified disease-associated mutants fail to form stable dimers. In conclusion, our data provide a mechanistic basis for the recognition of RNA fragments by TLR7.
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Project description:IRF5 and STAT4 are strongly associated with human systemic lupus erythematosus (SLE). By performing chromatin immunoprecipitation-sequencing (ChIP-Seq) in human peripheral blood mononuclear cells (PBMCs), we identified more than 7000 target genes for IRF5 and STAT4 in stimulated PBMCs. Contrarily, without stimulation IRF5 seemed to be inactive, and STAT4 only showed low levels of transcriptional regulatory activity.
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