An essential role for TASL in TLR signaling and autoimmune pathogenesis
The immune adaptor TASL mediates, through binding to SLC15A4, activation of the transcription factor IRF5 during Toll-like receptor (TLR) signaling. Single nucleotide polymorphisms (SNPs) within TASL have been linked with increased susceptibility to systemic lupus erythematosus (SLE), yet the biological function of TASL in vivo and its genetic relation to SLE pathogenesis is poorly understood. Using Tasl deficient mice and human cells derived from genetic carriers of the lupus risk SNP, rs887369-C, researchers have demonstrated a novel role for TASL in TLR7/9 signaling. Their data, published in Nature Communications, suggest a biological basis for SLE development associated with the rs887369-C risk variant.
TASL is essential for TLR7/9 induced cytokine production
To understand the biological function of TASL in vivo, Lau et al. administered various TLR ligands to wild-type and Tasl deficient mice and assessed serum cytokine and type I interferon levels by ELISA. Production of type I interferons in response to TLR7 and TLR9 agonists was observed in only the wild-type control group, suggesting a specific role for TASL in TLR7/9 signaling. This function of TASL was subsequently shown to be cell autonomous through the isolation of distinct cell types for TLR7/9 stimulation in vitro. Notably, the loss of TASL in splenic plasmacytoid dendritic cells (pDCs), B cells, and neutrophils resulted in a lack of IFN-β or IL-6 secretion in response to TLR7/9 stimulation.
Tasl deficient mice are resistant to SLE development
The role of TASL in SLE development in vivo was investigated using two different chemically induced mouse models of lupus: imiquimod, which induces systemic autoimmune disease and SLE-like symptoms in BALB/c mice following repeated epicutaneous application, and pristane, which leads to the production of autoantibodies. In both models, the wild-type controls developed autoimmune symptoms following treatment, while the Tasl deficient animals did not. These data point toward an essential role for TASL in SLE disease initiation.
Characterization of the lupus risk SNP, rs887369-C
The lupus risk SNP, rs887369-C, has a higher codon usage frequency (28.1%) than the A allele (11%), which could potentially increase susceptibility to SLE by enhancing TASL expression to augment cytokine production. To test this theory, Lau et al. performed a series of in vitro experiments. These included transfecting HEK293T cells with plasmid constructs encoding either the C or A allele and analyzing protein expression by Western blot, which showed cells expressing the C allele to exhibit consistently higher TASL protein levels compared to those expressing the A allele. CRISPR mediated deletion of TASL in primary human B cells was found to diminish cytokine production in response to TLR stimulation. In contrast, mRNA transfection of TASL in primary human B cells increased responses to TLR signaling relative to control CopGFP transfection. The mRNA that was used for this research was custom synthesized by TriLink.
Conclusion
This study demonstrates an essential role for TASL in TLR signaling and shows that SNPs affecting TASL expression may increase SLE risk due to enhanced TLR responsiveness. Agents that disrupt the SLC15A4-TASL-IRF5 signaling pathway could therefore represent a potential SLE treatment strategy.
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Article reference: Lau L, Cariaga TA, Chang AB, et al. An essential role for TASL in mouse autoimmune pathogenesis and Toll-like receptor signaling. Nat Commun 16, 968 (2025). https://www.nature.com/articles/s41467-024-55690-0