The role of TASL in the pathogenesis of SLE: X marks the spot.
The role of TASL in the pathogenesis of SLE: X marks the spot.
复制标题
TASL 在 SLE 发病机制中的作用：X 标记点。
DOI：
10.1136/annrheumdis-2020-218643
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发表时间：
2021
影响因子：
27.4
通讯作者：
Pisetsky,DavidS
中科院分区：
文献类型：
--
作者：
Pisetsky,DavidS
海因茨等人在《自然》杂志上发表的一篇开创性论文中提供了关于CXorf 21基因产物的重要新信息，CXorf 21是一种与系统性红斑狼疮（SLE）相关的X连锁基因。[1]这些研究人员使用一系列令人印象深刻的分子技术，证明了由最初称为CXorf 21的基因编码的蛋白质与SLC 15 A4相互作用，SLC 15 A4是内溶酶体区室中的氨基酸转运蛋白; SLC 15 A4的基因也与SLE遗传相关。虽然CXorf 21在SLE中的作用已被研究多年，但其蛋白产物的功能一直是个谜，直到海因茨等人将其鉴定为TLR信号传导中的衔接子。这种蛋白质的名称现在是“TLR适配器与内溶酶体SLC 15 A4相互作用”或TASL;该基因被命名为TASL（CXorf 21）。正如Nature论文中对THP 1和其他人类细胞的研究所示，TASL对于TLR 7，8和9下游信号传导中转录因子IRF 5的招募和激活非常重要;因此，TASL与衔接蛋白如STING，MAVS和TRIF具有相似性。这些发现与SLE的发病机制有关，因为在这种疾病中，DNA和RNA以免疫复合物的形式进入先天免疫系统的细胞，通过内体中的TLR 7、8和9诱导应答;干扰素和其他促炎细胞因子的产生是该途径的结果。有趣的是，在其基因表达的调节中，TASL影响IRF途径，但不影响NF-κB或MAPK信号传导。1这种模式表明TASL在通过内体TLR激活先天免疫中的独特作用（图1）。虽然TASL的功能在海因茨等人的论文中是新描述的，但SLC 15 A4的功能具有更长的历史。这种蛋白质在免疫信号传导中的作用最初是在小鼠体内筛选浆细胞样树突状细胞（pDC）功能所必需的蛋白质中描述的，浆细胞样树突状细胞（pDC）是产生1型干扰素的关键细胞类型。2在随机诱变后pDC发育或功能缺陷的小鼠中，指定为弱的菌株显示pDC响应于TLR 7和9的配体刺激而异常产生干扰素。然后将虚弱定位到Slc 15 a4中的突变，Slc 15 a4编码溶酶体隔室中的转运蛋白（这些基因和蛋白质的名称在出版物中有所不同，说明字母大写的一些差异）。SLC 15 A4在TLR信号传导中的作用现已被广泛研究。SLC 15 A4是一种质子偶联的氨基酸转运蛋白，可以将组氨酸和寡肽从溶酶体内转移到胞质溶胶中。3这种活性是在B细胞、单核细胞以及pDC中产生TLR 7和TLR 9刺激的亚细胞环境的关键。随着SLC 15 A4的丧失，内溶酶体pH调节受到干扰，干扰素和其他细胞因子的产生减少。在B细胞应答领域，SLC 15 A4的缺失可以防止致病性自身抗体的产生。事实上，对表达Slc 15 a4突变基因的自身免疫NZB和C57 BL/6-Faslpr小鼠的研究表明SLE的自身抗体产生减少和其他临床表现。4使用降植烷模型的其他研究表明，Slc 15 a4-/-小鼠具有抗snRNP和抗DNA的减少的产生，抗snRNP和抗DNA是SLE的自身抗体特征。然而，SLC 15 A4缺失不影响对LPS和具有表面受体的其它TLR配体的应答。3与SLC 15 A4的情况相反，该蛋白的功能是已知的，对CXorf 21作用的研究主要涉及遗传学。
In a seminal paper published in Nature, Heinz et al provide important new information on the gene product of CXorf21, an X-linked gene associated with systemic lupus erythematosus (SLE). 1 Using an impressive array of molecular techniques, these investigators demonstrated that the protein encoded by a gene originally known as CXorf21 interacts with SLC15A4, an amino acid transporter in the endolysosomal compartment; the gene for SLC15A4 has also been genetically associated with SLE. While the role of CXorf21 in SLE had been investigated for many years, the function of its protein product was a mystery until Heinz et al identified it as an adaptor in TLR signalling. The name for this protein is now ‘TLR adaptor interacting with endolysosomal SLC15A4’or TASL; the gene is designated as TASL (CXorf21). As the studies in THP1 and other human cells in the Nature paper illustrate, TASL is important for the recruitment and activation of the transcription factor IRF5 in downstream signalling by TLR 7, 8 and 9; as such, TASL has analogy with adaptor proteins like STING, MAVS and TRIF. These findings are relevant to the pathogenesis of SLE since, in this disease, DNA and RNA in the form of immune complexes can enter cells of the innate immune system to induce responses by TLR 7, 8 and 9 in the endosomes; the production of interferon and other proinflammatory cytokines is an outcome of this pathway. Interestingly, in its regulation of gene expression, TASL affects the IRF pathway but does not affect NF-κB or MAPK signalling. 1 This pattern points to a unique role of TASL in the activation of innate immunity by the endosomal TLRs (figure 1). While the function of TASL is newly described in the paper by Heinz et al, the function of SLC15A4 has a longer history. The role of this protein in immune signalling was originally described in an in vivo screen in the mouse for proteins necessary for the function of plasmacytoid dendritic cells (pDCs), a key cell type for the production of type 1 interferon. 2 Among mice with defects in either pDC development or function following random mutagenesis, a strain designated as feeble showed aberrant production of interferon by pDCs in response to stimulation by ligands of TLR7 and 9. Feeble was then mapped to a mutation in Slc15a4 which encodes a transport protein in the lysosomal compartment (the designation of these genes and proteins has varied among publications, accounting for some differences in capitalisation of the letters). The role of SLC15A4 in TLR signalling has now been extensively studied. SLC15A4 is a proton-coupled amino acid transporter that can move histidine and oligopeptides from inside the lysosome into the cytosol. 3 This activity is key to the creation of a subcellular environment for stimulation by TLR 7 and TLR 9 in B cells, monocytes as well as pDCs. With a loss of SLC15A4, endolysosomal pH regulation is disturbed and the production of interferon and other cytokines is reduced. In the realm of B cell responses, loss of SLC15A4 can prevent pathogenic autoantibody production. Indeed, studies on autoimmune NZB and C57BL/6-Faslpr mice expressing a Slc15a4 mutant gene indicate reduced autoantibody production and other clinical manifestations of SLE. 4 Other studies using the pristane model of SLE indicated that the Slc15a4-/-mice have reduced production of anti-snRNP and anti-DNA, autoantibodies characteristic of SLE. SLC15A4 loss, however, does not affect the response to LPS and other TLR ligands with surface receptors. 3 In contrast to the situation with SLC15A4, where the function of the protein was known, studies on the role of CXorf21 primarily involved genetic …