SLC15A4:TASL-dependent IRF5 activation

Solute carrier family 15, member 4 (SLC15A4, also known as PHT1) is a proton-coupled L-histidine/oligopeptide transporter. In addition to its function as a transporter, SLC15A4 regulates TLR7-9 signaling pathways in late endosomes/lysosomes (Heinz LX. et al., 2020; Kobayashi T et al., 2021). SLC15A4 acts as a signaling scaffold, recruiting the protein TLR adaptor interacting with SLC15A4 on the lysosome (TASL) to the cytosolic surface of endolysosomes (Heinz LX. et al., 2020; Custodio TF et al., 2023; Chen X et al., 2023). Upon activation of endosomal TLR signaling, TASL undergoes phosphorylation and recruits IRF5 to its pLxIS motif (Heinz LX. et al., 2020). The SLC15A4:TASL complex facilitates IRF5 phosphorylation by IKBKB (IKKβ) and subsequent IRF5 homodimerization downstream of TLR7-TLR9 (Heinz LX. et al., 2020; Zhang H et al., 2023; Chen X et al., 2023; Boeszoermeny A et al., 2023). Once activated, IRF5 translocates to the nucleus to induce the transcription of genes encoding type I interferons (IFNs) and pro-inflammatory cytokines. Hyperactivation of the SLC15A4:TASL:IRF5 pathway, often caused by the detection of endogenous nucleic acids, leads to increased production of type I IFNs and is associated with pathogenesis of inflammatory diseases such as systemic lupus erythematosus (SLE) (Odhams CA et al., 2019; Heinz LX. et al., 2020; Kobayashi T et al., 2021).