Human SLC15A4 is crucial for TLR-mediated type I interferon production and mitochondrial integrity
Human SLC15A4 is crucial for TLR-mediated type I interferon production and mitochondrial integrity
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DOI：
10.1093/intimm/dxab006
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发表时间：
2021-02-09
影响因子：
4.4
通讯作者：
Toyama-Sorimachi, Noriko
中科院分区：
文献类型：
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作者：
Kobayashi, Toshihiko;Nguyen-Tien, Dat;Toyama-Sorimachi, Noriko
溶质载体家族成员4(SLC15A4)是一种驻留在内溶酶体上的氨基酸转运体，调节先天免疫反应，与系统性红斑狼疮(SLE)和结肠炎等炎症性疾病有关。SLC15A4基因缺陷小鼠表现出上述模型疾病症状的改善，因此SLC15A4是治疗SLE和结肠炎的有前途的靶点。为了开发基于SLC15A4的治疗策略，了解人类SLC15A4的S特性是至关重要的。在这里，我们对人SLC15A4进行了鉴定，并证明了人SLC15A4对二肽或三肽的转运具有pH和温度依赖性的活性。人SLC15A4定位于LAMP1(+)区，与猛禽和LAMTOR密切相关。我们还利用人浆细胞样树突状细胞系CAL-1研究了SLC15A4‘S在炎症反应中的作用。CAL-1(SLC15A4-KD CAL-1)中SLC15A4基因的敲除(KD)可抑制Toll样受体(TLR)7/8或TLR9触发的I型干扰素(IFN-I)的产生和mTORC1活性，表明人SLC15A4在TLR7/8/9介导的炎症信号转导中起关键作用。我们还检测了SLC15A4在自噬反应中的S作用，因为SLC15A4的缺失导致mTORC1活性降低，这对自噬有很大的影响。我们发现SLC15A4不是自噬诱导所必需的，但对自噬的可持续性至关重要。值得注意的是，SLC15A4-KD CAL-1在饥饿条件下严重降低线粒体膜电位。我们的发现揭示了SLC15A4在人类细胞线粒体完整性中的关键作用，这可能有助于免疫细胞在炎症环境中履行其功能。
Solute carrier family 15 member 4 (SLC15A4) is an endolysosome-resident amino acid transporter that regulates innate immune responses, and is genetically associated with inflammatory diseases such as systemic lupus erythematosus (SLE) and colitis. SLC15A4-deficient mice showed the amelioration of symptoms of these model diseases, and thus SLC15A4 is a promising therapeutic target of SLE and colitis. For developing a SLC15A4-based therapeutic strategy, understanding human SLC15A4's properties is essential. Here, we characterized human SLC15A4 and demonstrated that human SLC15A4 possessed pH- and temperature-dependent activity for the transportation of dipeptides or tripeptides. Human SLC15A4 localized in LAMP1(+) compartments and constitutively associated with Raptor and LAMTORs. We also investigated SLC15A4's role in inflammatory responses using the human plasmacytoid dendritic cell line, CAL-1. Knock down (KD) of the SLC15A4 gene in CAL-1 (SLC15A4-KD CAL-1) impaired Toll-like receptor (TLR) 7/ 8 or TLR9-triggered type I interferon (IFN-I) production and mTORC1 activity, indicating that human SLC15A4 is critical for TLR7/8/9-mediated inflammatory signaling. We also examined SLC15A4's role in the autophagy response since SLC15A4 loss caused the decrease of mTORC1 activity, which greatly influences autophagy. We found that SLC15A4 was not required for autophagy induction, but was critical for autophagy sustainability. Notably, SLC15A4-KD CAL-1 severely decreased mitochondrial membrane potential in starvation conditions. Our findings revealed that SLC15A4 plays a key role in mitochondrial integrity in human cells, which might benefit immune cells in fulfilling their functions in an inflammatory milieu.