The solute carrier SLC15A4 is required for optimal trafficking of nucleic acid-sensing TLRs and ligands to endolysosomes.
The solute carrier SLC15A4 is required for optimal trafficking of nucleic acid-sensing TLRs and ligands to endolysosomes.
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DOI：
10.1073/pnas.2200544119
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发表时间：
2022-04-05
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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作者：
大量证据表明，内体Toll样受体（TLR）对自身核酸的识别是自发性小鼠模型中狼疮样系统性自身免疫发病机制的核心，而溶质载体SLC15A4是这种识别所必需的。在这里，我们描述了一种机制，其中 SLC15A4 是 TLR 及其配体正确运输到内溶酶体的主要贡献者，识别和信号传导是在其中启动的。这一发现支持了持续不断的努力，以确定这种载体的药理学抑制剂作为治疗狼疮和其他炎症性疾病的手段。 SLC15A4 的功能损害突变（微弱）或基因组缺失会消除核酸感应内体 Toll 样受体 (TLR) 的反应，并显着减少狼疮小鼠模型的疾病。在这里，我们证明了具有 Tlr7 基因重复的纯合子甚至杂合子 Slc15a4 弱突变 BXSB 雄性小鼠的疾病减少。与SLC15A4相反，SLC15A3的功能受损突变并没有减少TLR激活的浆细胞样树突状细胞(pDC)产生I型干扰素(IFN-I)，这表明这些同源SLC15家族成员之间的功能存在差异。 SLC15A4 向内溶酶体的运输和功能依赖于衔接蛋白 3 (AP-3) 复合物。重要的是，SLC15A4 是核酸感应 TLR 及其配体运输和共定位到内溶酶体以及形成 LAMP2+VAMP3+ 杂交区室（其中启动 IFN-I 产生）所必需的。总的来说，这些发现定义了 SLC15A4 控制内体 TLR 功能的机制过程，并表明削弱该转运蛋白功能的药物干预可能是治疗狼疮和其他内体 TLR 依赖性疾病的一种手段。
A large body of evidence has indicated that recognition of self-nucleic acids by endosomal toll-like receptors (TLRs) is central to the pathogenesis of lupus-like systemic autoimmunity in spontaneous mouse models, and the solute carrier SLC15A4 is required for this recognition. Here we describe a mechanism in which SLC15A4 is a major contributor to the proper trafficking of TLRs and their ligands to endolysosomes, wherein recognition and signaling is initiated. This finding supports ongoing efforts to identify pharmacologic inhibitors for this carrier as a means to treat lupus and other inflammatory disorders. A function-impairing mutation (feeble) or genomic deletion of SLC15A4 abolishes responses of nucleic acid–sensing endosomal toll-like receptors (TLRs) and significantly reduces disease in mouse models of lupus. Here, we demonstrate disease reduction in homozygous and even heterozygous Slc15a4 feeble mutant BXSB male mice with a Tlr7 gene duplication. In contrast to SLC15A4, a function-impairing mutation of SLC15A3 did not diminish type I interferon (IFN-I) production by TLR-activated plasmacytoid dendritic cells (pDCs), indicating divergence of function between these homologous SLC15 family members. Trafficking to endolysosomes and function of SLC15A4 were dependent on the Adaptor protein 3 (AP-3) complex. Importantly, SLC15A4 was required for trafficking and colocalization of nucleic acid–sensing TLRs and their ligands to endolysosomes and the formation of the LAMP2+VAMP3+ hybrid compartment in which IFN-I production is initiated. Collectively, these findings define mechanistic processes by which SLC15A4 controls endosomal TLR function and suggest that pharmacologic intervention to curtail the function of this transporter may be a means to treat lupus and other endosomal TLR-dependent diseases.
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影响因子：
4.4
作者：
Lewis, Colleen J.;Cobb, Brian A.
通讯作者：
Cobb, Brian A.
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影响因子：
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影响因子：
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作者：
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DOI：
10.4049/jimmunol.1201477
发表时间：
2012-12-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Baccala R;Gonzalez-Quintial R;Schreiber RD;Lawson BR;Kono DH;Theofilopoulos AN
通讯作者：
Theofilopoulos AN
DOI：
10.1038/nrd4626
发表时间：
2015-08
期刊：
Nature reviews. Drug discovery
影响因子：
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