The TLR7/9 adaptors TASL and TASL2 mediate IRF5-dependent antiviral responses and autoimmunity in mouse.
Details
Serval ID
serval:BIB_5CCF71D82E31
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
The TLR7/9 adaptors TASL and TASL2 mediate IRF5-dependent antiviral responses and autoimmunity in mouse.
Journal
Nature communications
ISSN
2041-1723 (Electronic)
ISSN-L
2041-1723
Publication state
Published
Issued date
24/01/2025
Peer-reviewed
Oui
Volume
16
Number
1
Pages
967
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Publication Status: epublish
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 (TASL <sup>DKO</sup> ) phenocopies SLC15A4-deficient feeble mice showing comparable impairment of innate and humoral responses. Consequently, TASL <sup>DKO</sup> 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.
Keywords
Animals, Toll-Like Receptor 7/metabolism, Toll-Like Receptor 7/genetics, Toll-Like Receptor 7/immunology, Mice, Knockout, Mice, Toll-Like Receptor 9/metabolism, Toll-Like Receptor 9/genetics, Autoimmunity, Mice, Inbred C57BL, Lupus Erythematosus, Systemic/immunology, Lupus Erythematosus, Systemic/genetics, Immunity, Innate, Humans, Membrane Transport Proteins/metabolism, Membrane Transport Proteins/genetics, Interferon Regulatory Factors/metabolism, Interferon Regulatory Factors/genetics, Adaptor Proteins, Signal Transducing/genetics, Adaptor Proteins, Signal Transducing/metabolism, Adaptor Proteins, Signal Transducing/immunology, Lymphocytic choriomeningitis virus/immunology, Female, Membrane Glycoproteins
Pubmed
Open Access
Yes
Funding(s)
Swiss National Science Foundation / 310030_200709
Swiss National Science Foundation / 310030_200709
Swiss National Science Foundation / 310030_200709
Create date
27/01/2025 9:48
Last modification date
28/01/2025 7:13