Journal Article

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

Marquis, Julien, Calderon Copete, Sandra, Royer-Chardon, Claire, Rotman, Samuel, Bernaleau, Léa, Longepierre, Mélissa, Rebsamen, Manuele, Drobek, Ales, Monguió-Tortajada, Marta, Korzeniowski, Jakub, Delacrétaz, Maeva

2025

Overview

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 (TASL DKO ) phenocopies SLC15A4-deficient feeble mice showing comparable impairment of innate and humoral responses. Consequently, TASL DKO 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. TASL is an adaptor molecule bridging Toll-like receptor signalling and transcription activation by IRF5. Here the authors show that TASL deficiency impacts TLR7/9 responses, and that a TASL paralogue, Gm6377/TASL2, also contributes to IRF5 activation, as dual TASL/TASL2 deficiency dampens both protective and pathogenic inflammatory responses in mice.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/31 / 13/95 / 631/250/2502 / 631/250/2504 / 631/250/262/2106/2108 / 631/250/38 / 64/60 / 96/21 / Adapters / Adaptor proteins / Animals / Antiviral drugs / Autoimmunity / Cell activation / Chronic conditions / Chronic infection / Cytokines / Disease / Disease Models, Animal / Female / Humanities and Social Sciences / Humans / Immune system / Immunity, Innate / Impairment / Interferon Regulatory Factors - genetics / Interferon Regulatory Factors - immunology / Interferon Regulatory Factors - metabolism / Ligands / Lupus Erythematosus, Systemic - chemically induced / Lupus Erythematosus, Systemic - genetics / Lupus Erythematosus, Systemic - immunology / Membrane Glycoproteins - immunology / Membrane Glycoproteins - metabolism / Membrane Transport Proteins - genetics / Membrane Transport Proteins - immunology / Membrane Transport Proteins - metabolism / Mice / Mice, Inbred C57BL / Mice, Knockout / multidisciplinary / Nucleic acids / Phosphorylation / Pristane / Proteins / Science / Science (multidisciplinary) / Systemic lupus erythematosus / Terpenes / TLR7 protein / TLR9 protein / Toll-Like Receptor 7 - genetics / Toll-Like Receptor 7 - immunology / Toll-Like Receptor 7 - metabolism / Toll-Like Receptor 9 - genetics / Toll-Like Receptor 9 - immunology / Toll-Like Receptor 9 - metabolism / Toll-like receptors / Transcription activation