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

Endolysosomal Toll-like receptors (TLRs) play crucial roles in immune responses to pathogens, while aberrant activation of these pathways is associated with autoimmune diseases, including systemic lupus erythematosus (SLE). The endolysosomal solute carrier family 15 member 4 (SLC15A4) is required for TLR7/8/9-induced responses and disease development in SLE models. SLC15A4 has been proposed to affect TLR7–9 activation through its transport activity, as well as by assembling an IRF5-activating complex with TASL, but the relative contribution of these functions remains unclear. Here, we show that the essential role of SLC15A4 is to recruit TASL to endolysosomes, while its transport activity is dispensable when TASL is tethered to this compartment. Endolysosomal-localized TASL rescues TLR7–9-induced IRF5 activation as well as interferon β and cytokine production in SLC15A4-deficient cells. SLC15A4 acts as signaling scaffold, and this function is essential to control TLR7–9-mediated inflammatory responses. These findings support targeting the SLC15A4-TASL complex as a potential therapeutic strategy for SLE and related diseases

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

SUMMARYNucleic 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.</jats:p

Semi-automated workflows to quantify AAV transduction in various brain areas and predict gene editing outcome for neurological disorders

One obstacle to the development of gene therapies for the central nervous system is the lack of workflows for quantifying transduction efficiency in affected neural networks and ultimately predicting therapeutic potential. We integrated data from a brain cell atlas with 3D or 2D semi-automated quantification of transduced cells in segmented images to predict AAV transduction efficiency in multiple brain regions. We used this workflow to estimate the transduction efficiency of AAV2/rh.10 and AAV2.retro co-injection in the corticostriatal network affected in Huntington’s disease. We then validated our pipeline in gene editing experiments targeting both human and mouse huntingtin genes in transgenic and wild-type mice, respectively. Our analysis predicted that 54% of striatal cells and 7% of cortical cells would be edited in highly transduced areas. Remarkably, in the treated animals, huntingtin gene inactivation reached 54.5% and 9.6%, respectively. These results demonstrate the power of this workflow to predict transduction efficiency and the therapeutic potential of gene therapies in the central nervous system