SLC15A4 controls endolysosomal TLR7-9 responses by recruiting the innate immune adaptor TASL

SUMMARY Nucleic acid sensing by endolysosomal Toll-like receptors (TLRs) plays a crucial role in innate immune responses to invading pathogens. In contrast, aberrant activation of these pathways is associated with several autoimmune diseases, such as systemic lupus erythematosus (SLE). The endolysosomal solute carrier family 15 member 4 (SLC15A4) is required for TLR7, TLR8 and TLR9-induced inflammatory responses and for disease development in different SLE models. SLC15A4 has been proposed to affect TLR7-9 activation through its transport activity, as well as by assembling in an IRF5-activating signalling complex with the innate immune adaptor TASL, but the relative contribution of these different functions remains unclear. Here we show that the essential role of SLC15A4 is to recruit TASL to the endolysosomal compartment, while its transport activity is dispensable. Targeting of TASL to the endolysosomal compartment is sufficient to rescue TLR7-9-induced IRF5 activation in SLC15A4-deficient cells. In line with this, lysosomal-localized TASL restored proinflammatory cytokines and type I interferon responses in absence of SLC15A4. Our study reveals that SLC15A4 acts as a signalling scaffold and that this transport-independent function is essential to control TLR7-9-mediated inflammatory responses. These findings further support targeting the SLC15A4-TASL complex as a potential therapeutic strategy for SLE and related diseases.