SLC15A4 binds TASL

Solute carrier family 15 member 4 protein (SLC15A4, also known as PHT1) and TLR adaptor interacting with SLC15A4 on the lysosome (TASL) control the activation of the key transcription factor IRF5 in response to activation of endosomal Toll-like receptors (TLR7, TLR8, and TLR9) (Heinz L et al., 2020; Zhang H et al., 2023). TASL is recruited to SLC15A4, located on the endolysosomal membrane (Heinz L et al., 2020; Zhang H et al., 2023; Chen X et al., 2023; Boeszoermeny A et al., 2023). Structural studies using cryo-electron microscopy (cryo-EM) reveal that formation of the human SLC15A4:TASL complex involves transition of SLC15A4 from the endolysosomal lumen-exposed outward-facing apo state to an inward-facing state in which the negatively-charged binding pocket of SLC15A4 facilitates the insertion of the N-terminal helix of TASL (Chen X et al., 2023; Boeszoermeny A et al., 2023). Mutagenesis analysis further confirms that the N-terminus of TASL interacts with SLC15A4 (Heinz L et al., 2020; Zhang H et al., 2023; Boeszoermeny A et al., 2023; Chen X et al., 2023). Similar findings have been reported for chicken SLC15A4 and TASL (Custodio TF et al., 2023). The formation of SLC15A4:TASL complex is required for endosomal TLR-induced IRF5 activation, and subsequent translocation of activated IRF5 to the nucleus (Heinz L et al., 2020; Zhang H et al., 2023; Chen X et al., 2023; Boeszoermeny A et al., 2023). Disruption of the SLC15A4:TASL complex abolishes TLR-induced IRF5 activation (Heinz L. et al., 2020; Zhang H et al., 2023; Chen X et al., 2023; Boeszoermeny A et al., 2023).<br>

溶质载体家族15成员4蛋白（SLC15A4，亦称PHT1）及与溶酶体上SLC15A4相互作用的TLR适配体（TASL）调控着对内体Toll样受体（TLR7、TLR8和TLR9）激活后的关键转录因子IRF5的激活（Heinz L et al., 2020; Zhang H et al., 2023）。TASL被募集至位于内体溶酶体膜上的SLC15A4（Heinz L et al., 2020; Zhang H et al., 2023; Chen X et al., 2023; Boeszoermeny A et al., 2023）。利用冷冻电子显微镜（cryo-EM）进行的结构研究揭示了人类SLC15A4:TASL复合物的形成涉及SLC15A4从暴露于内体溶酶体腔的向外开放的无活性形式（apo state）向面向内腔的状态转变，其中SLC15A4的带负电荷的结合口袋促进了TASL的N端螺旋的插入（Chen X et al., 2023; Boeszoermeny A et al., 2023）。突变分析进一步证实了TASL的N端与SLC15A4的相互作用（Heinz L et al., 2020; Zhang H et al., 2023; Boeszoermeny A et al., 2023; Chen X et al., 2023）。类似的结果已在鸡的SLC15A4和TASL的研究中得到报道（Custodio TF et al., 2023）。SLC15A4:TASL复合物的形成对于内体TLR诱导的IRF5激活及其后续激活的IRF5向细胞核的转位是必需的（Heinz L et al., 2020; Zhang H et al., 2023; Chen X et al., 2023; Boeszoermeny A et al., 2023）。SLC15A4:TASL复合体的破坏消除了TLR诱导的IRF5激活（Heinz L. et al., 2020; Zhang H et al., 2023; Chen X et al., 2023; Boeszoermeny A et al., 2023）。