SLC15A4 is an endolysosome-resident transporter linked with autoinflammation and autoimmunity. Specifically, SLC15A4 is critical for Toll-like receptors (TLRs) 7–9 as well as nucleotide-binding oligomerization domain-containing protein (NOD) signaling in several immune cell subsets. Notably, SLC15A4 is essential for the development of systemic lupus erythematosus in murine models and is associated with autoimmune conditions in humans. Despite its therapeutic potential, the availability of quality chemical probes targeting SLC15A4 functions is limited. In this study, we used an integrated chemical proteomics approach to develop a suite of chemical tools, including first-in-class functional inhibitors, for SLC15A4. We demonstrate that these inhibitors suppress SLC15A4-mediated endolysosomal TLR and NOD functions in a variety of human and mouse immune cells; we provide evidence of their ability to suppress inflammation in vivo and in clinical settings; and we provide insights into their mechanism of action. Our findings establish SLC15A4 as a druggable target for the treatment of autoimmune and autoinflammatory conditions.

SLC15A4 是一种与自身炎症和自身免疫相关的内溶酶体转运蛋白。具体来说，SLC15A4 对于 Toll 样受体 (TLR) 7-9 以及多个免疫细胞亚群中的核苷酸结合寡聚化结构域蛋白 (NOD) 信号转导至关重要。值得注意的是，SLC15A4 对于小鼠模型中系统性红斑狼疮的发展至关重要，并且与人类自身免疫性疾病相关。尽管具有治疗潜力，但针对 SLC15A4 功能的优质化学探针的可用性仍然有限。在这项研究中，我们使用综合化学蛋白质组学方法开发了一套针对 SLC15A4 的化学工具，包括一流的功能抑制剂。我们证明这些抑制剂可抑制多种人和小鼠免疫细胞中 SLC15A4 介导的内溶酶体 TLR 和 NOD 功能；我们提供证据证明它们在体内和临床环境中抑制炎症的能力；我们提供了对其作用机制的见解。我们的研究结果确立了 SLC15A4 作为治疗自身免疫和自身炎症性疾病的药物靶点。