Identification of lipophilic ligands of Siglec5 and -14 that modulate innate immune responses
Identification of lipophilic ligands of Siglec5 and -14 that modulate innate immune responses
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DOI：
10.1074/jbc.ra119.009835
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发表时间：
2019-09
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通讯作者：
R. Suematsu;T. Miyamoto;S. Saijo;S. Yamasaki;Y. Tada;H. Yoshida;Yasunobu Miyake
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作者：
R. Suematsu;T. Miyamoto;S. Saijo;S. Yamasaki;Y. Tada;H. Yoshida;Yasunobu Miyake
唾液酸结合免疫球蛋白样凝集素（Siglecs）是在末端聚糖残基处结合唾液酸的细胞表面免疫受体家族。Siglecs还识别非唾液酸配体，其中许多仍有待表征。在这里，我们发现Siglec 5和Siglec 14识别由发癣菌产生的脂质化合物，发癣菌是一种含有几种致病物种的真菌属。生物化学方法显示Siglec配体是真菌烷烃和三酰基甘油，这是一个意想不到的发现，促使我们寻找Siglec的内源性脂质配体。Siglec 5弱识别几种内源性脂质，但线粒体脂质心磷脂和抗炎脂质5-棕榈酸-羟基硬脂酸对Siglec 5表现出有效的配体活性。此外，发现Siglec 5 N末端区域中的疏水延伸是有效识别这些脂质所需的。值得注意的是，这种疏水性的延伸被用于识别唾液酸。Siglec 5在配体结合时抑制细胞活化，因此，亲脂性配体抑制表达Siglec 5的人单核细胞中的白细胞介素-8（IL-8）产生。Siglec 14和Siglec 5在细胞外区域具有高度的序列同一性，并且Siglec 14还识别内源性脂质。然而，与Siglec 5不同，Siglec 14在配体识别后转导激活信号。事实上，内源性脂质诱导表达Siglec 14的人单核细胞中的IL-8产生。这些结果表明Siglec 5和Siglec 14可以识别亲脂性配体，从而调节先天免疫应答。据我们所知，这是第一个报道Siglecs与脂质配体结合的研究，扩大了我们对Siglecs在先天免疫中的生物学功能和重要性的理解。
Sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of cell-surface immune receptors that bind to sialic acid at terminal glycan residues. Siglecs also recognize nonsialic acid ligands, many of which remain to be characterized. Here, we found that Siglec5 and Siglec14 recognize lipid compounds produced by Trichophyton, a fungal genus containing several pathogenic species. Biochemical approaches revealed that the Siglec ligands are fungal alkanes and triacylglycerols, an unexpected finding that prompted us to search for endogenous lipid ligands of Siglecs. Siglec5 weakly recognized several endogenous lipids, but the mitochondrial lipid cardiolipin and the anti-inflammatory lipid 5-palmitic acid-hydroxystearic acid exhibited potent ligand activity on Siglec5. Further, the hydrophobic stretch in the Siglec5 N terminus region was found to be required for efficient recognition of these lipids. Notably, this hydrophobic stretch was dispensable for recognition of sialic acid. Siglec5 inhibited cell activation upon ligand binding, and accordingly, the lipophilic ligands suppressed interleukin-8 (IL-8) production in Siglec5-expressing human monocytic cells. Siglec14 and Siglec5 have high sequence identity in the extracellular region, and Siglec14 also recognized the endogenous lipids. However, unlike Siglec5, Siglec14 transduces activating signals upon ligand recognition. Indeed, the endogenous lipids induced IL-8 production in Siglec14-expressing human monocytic cells. These results indicated that Siglec5 and Siglec14 can recognize lipophilic ligands that thereby modulate innate immune responses. To our knowledge, this is the first study reporting the binding of Siglecs to lipid ligands, expanding our understanding of the biological function and importance of Siglecs in the innate immunity.