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TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9

机译：TASL是TLR7-9的SLC15A4相关适配器，用于IRF5激活

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The interaction between TASL and SLC15A4 links endolysosomal Toll-like receptors to the transcription factor IRF5, providing a mechanistic explanation for the involvement of the complex in systemic lupus erythematosus.Toll-like receptors (TLRs) have a crucial role in the recognition of pathogens and initiation of immune responses(1-3). Here we show that a previously uncharacterized protein encoded by CXorf21-a gene that is associated with systemic lupus erythematosus(4,5)-interacts with the endolysosomal transporter SLC15A4, an essential but poorly understood component of the endolysosomal TLR machinery also linked to autoimmune disease(4,6-9). Loss of this type-I-interferon-inducible protein, which we refer to as 'TLR adaptor interacting with SLC15A4 on the lysosome' (TASL), abrogated responses to endolysosomal TLR agonists in both primary and transformed human immune cells. Deletion of SLC15A4 or TASL specifically impaired the activation of the IRF pathway without affecting NF-kappa B and MAPK signalling, which indicates that ligand recognition and TLR engagement in the endolysosome occurred normally. Extensive mutagenesis of TASL demonstrated that its localization and function relies on the interaction with SLC15A4. TASL contains a conserved pLxIS motif (in which p denotes a hydrophilic residue and x denotes any residue) that mediates the recruitment and activation of IRF5. This finding shows that TASL is an innate immune adaptor for TLR7, TLR8 and TLR9 signalling, revealing a clear mechanistic analogy with the IRF3 adaptors STING, MAVS and TRIF10,11. The identification of TASL as the component that links endolysosomal TLRs to the IRF5 transcription factor via SLC15A4 provides a mechanistic explanation for the involvement of these proteins in systemic lupus erythematosus(12-14).
机译：Tas1和SLC15A4之间的相互作用将底糖瘤性收缩的受体链接到转录因子IRF5，为综合体在系统性红斑狼疮中的参与提供机械解释。类似于受体（TLR）在识别病原体中具有至关重要的作用引发免疫应答（1-3）。在这里，我们表明，通过CXORF21-A基因编码的先前无特异化的蛋白质，其与全身狼疮红斑（4,5） - 与底糖体转运蛋白SLC15A4相互作用，是底糖瘤性TLR机械的必要但不知情的组分也与自身免疫疾病有关（4,6-9）。丧失这种类型-I-干扰素诱导蛋白质，我们将其称为“与溶酶体组（Tas1）上的SLC15A4相互作用的TLR适配器，废除对初级和转化的人免疫细胞中的底溶解剂TLR激动剂的反应。 SLC15A4或TASL的缺失特异性地损害了IRF途径的激活而不影响NF-Kappa B和MAPK信号传导，这表明正常情况下的配体识别和TLR接合发生。 TASL的广泛诱变证明其本地化和功能依赖于与SLC15A4的相互作用。 TasL含有保守的PLXI基序（其中P表示亲水残留物，x表示任何残留物），其介导IRF5的募集和活化。该发现表明，TASL是TLR7，TLR8和TLR9信号传导的先天免疫适配器，揭示了与IRF3适配器STING，MAVS和TRIF10,11的透明机械类比。作为通过SLC15A4将底糖组织TLR链接到IRF5转录因子的组分的鉴定提供了用于涉及这些蛋白质在全身狼疮红斑（12-14）中的机械解释。

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