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The TLR7/9 adaptors TASL and TASL2 mediate IRF5-dependent antiviral responses and autoimmunity in mouse

Author

Listed:
  • Ales Drobek

    (University of Lausanne)

  • Léa Bernaleau

    (University of Lausanne)

  • Maeva Delacrétaz

    (University of Lausanne)

  • Sandra Calderon Copete

    (University of Lausanne)

  • Claire Royer-Chardon

    (Lausanne University Hospital (CHUV))

  • Mélissa Longepierre

    (University of Lausanne)

  • Marta Monguió-Tortajada

    (University of Lausanne)

  • Jakub Korzeniowski

    (University of Lausanne)

  • Samuel Rotman

    (Lausanne University Hospital (CHUV))

  • Julien Marquis

    (University of Lausanne)

  • Manuele Rebsamen

    (University of Lausanne)

Abstract

Endosomal nucleic acid sensing by Toll-like receptors (TLRs) is central to antimicrobial immunity and several autoimmune conditions such as systemic lupus erythematosus (SLE). The innate immune adaptor TASL mediates, via the interaction with SLC15A4, the activation of IRF5 downstream of human TLR7, TLR8 and TLR9, but the pathophysiological functions of this axis remain unexplored. Here we show that SLC15A4 deficiency results in a selective block of TLR7/9-induced IRF5 activation, while loss of TASL leads to a strong but incomplete impairment, which depends on the cell type and TLR engaged. This residual IRF5 activity is ascribed to a previously uncharacterized paralogue, Gm6377, named here TASL2. Double knockout of TASL and TASL2 (TASLDKO) phenocopies SLC15A4-deficient feeble mice showing comparable impairment of innate and humoral responses. Consequently, TASLDKO mice fail to control chronic LCMV infection, while being protected in a pristane-induced SLE disease model. Our study thus demonstrates the critical pathophysiological role of SLC15A4 and TASL/TASL2 for TLR7/9-driven inflammatory responses, further supporting the therapeutic potential of targeting this complex in SLE and related diseases.

Suggested Citation

  • Ales Drobek & Léa Bernaleau & Maeva Delacrétaz & Sandra Calderon Copete & Claire Royer-Chardon & Mélissa Longepierre & Marta Monguió-Tortajada & Jakub Korzeniowski & Samuel Rotman & Julien Marquis & M, 2025. "The TLR7/9 adaptors TASL and TASL2 mediate IRF5-dependent antiviral responses and autoimmunity in mouse," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55692-y
    DOI: 10.1038/s41467-024-55692-y
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