The SLC15A4–TASL complex is essential for lupus development in mice

Abstract

Nucleic acid sensing by endolysosomal Toll-like receptors is critically involved in systemic lupus erythematosus (SLE) and related autoimmune diseases. Downstream of TLR7, TLR8, and TLR9, the SLE-associated SLC15A4–TASL complex selectively mediates IRF5 activation, while being dispensable for NF-κB and MAPK pathways. Here, we show that the SLC15A4–TASL signaling axis is broadly required for disease development and pathogenesis across three complementary genetic SLE models, reflecting different etiologies. Genetic ablation of Tasl ( Tasl KO ) and its paralogue Tasl2 ( Tasl DKO ) ameliorated or fully prevented autoimmune manifestations resulting from Fas lpr loss of function, respectively. Furthermore, SLC15A4–TASL complex deficiency was sufficient to protect from disease, including splenomegaly, immune activation, and autoantibody formation, driven by the patient-derived Tlr7 Y264H gain-of-function mutation, even in the presence of functional NF-κB and MAPK responses. Last, Tasl DKO splenocyte transfer into lymphopenic Dnase1l3 -deficient mice demonstrated that protection extends to DNA-driven autoimmunity, in which TLR7 and TLR9 act redundantly, strongly supporting a B cell–intrinsic role. Notably, SLC15A4–TASL complex deficiency blunted the generation of pathogenic age-associated B cells in all three autoimmune models as well as in aged animals. Collectively, these data demonstrate the central role of the SLC15A4–TASL complex in SLE, supporting its potential as therapeutic target.

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BibTeX

@article{drobek2026slc15a4tasl,
  title = {{The SLC15A4–TASL complex is essential for lupus development in mice}},
  author = {Ales Drobek and Maeva Delacrétaz and Aliki Vasilakou and Marta Monguió-Tortajada and Léa Bernaleau and Maxime Dubois and Vanja Sisirak and Manuele Rebsamen},
  journal = {Proceedings of the National Academy of Sciences of the United States of America},
  year = {2026},
  month = sep,
  doi = {10.1073/pnas.2618215123},
  url = {https://u-bordeaux.hal.science/hal-05749219v1},
  note = {CC BY 4.0},
}

RIS

TY  - JOUR
TI  - The SLC15A4–TASL complex is essential for lupus development in mice
AU  - Ales Drobek
AU  - Maeva Delacrétaz
AU  - Aliki Vasilakou
AU  - Marta Monguió-Tortajada
AU  - Léa Bernaleau
AU  - Maxime Dubois
AU  - Vanja Sisirak
AU  - Manuele Rebsamen
PY  - 2026
DA  - 2026/09/01
JO  - Proceedings of the National Academy of Sciences of the United States of America
DO  - 10.1073/pnas.2618215123
UR  - https://u-bordeaux.hal.science/hal-05749219v1
AB  - Nucleic acid sensing by endolysosomal Toll-like receptors is critically involved in systemic lupus erythematosus (SLE) and related autoimmune diseases. Downstream of TLR7, TLR8, and TLR9, the SLE-associated SLC15A4–TASL complex selectively mediates IRF5 activation, while being dispensable for NF-κB and MAPK pathways. Here, we show that the SLC15A4–TASL signaling axis is broadly required for disease development and pathogenesis across three complementary genetic SLE models, reflecting different etiologies. Genetic ablation of Tasl ( Tasl KO ) and its paralogue Tasl2 ( Tasl DKO ) ameliorated or fully prevented autoimmune manifestations resulting from Fas lpr loss of function, respectively. Furthermore, SLC15A4–TASL complex deficiency was sufficient to protect from disease, including splenomegaly, immune activation, and autoantibody formation, driven by the patient-derived Tlr7 Y264H gain-of-function mutation, even in the presence of functional NF-κB and MAPK responses. Last, Tasl DKO splenocyte transfer into lymphopenic Dnase1l3 -deficient mice demonstrated that protection extends to DNA-driven autoimmunity, in which TLR7 and TLR9 act redundantly, strongly supporting a B cell–intrinsic role. Notably, SLC15A4–TASL complex deficiency blunted the generation of pathogenic age-associated B cells in all three autoimmune models as well as in aged animals. Collectively, these data demonstrate the central role of the SLC15A4–TASL complex in SLE, supporting its potential as therapeutic target.
SN  - 0027-8424
SN  - 1091-6490
ER  -

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