Faculty of Nursing, School of Medicine, Tokai University, Kanagawa 259-1193, Japan.
Department of Epigenetics, Medical Research Institute (MRI), Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan.
Development. 2022 Sep 15;149(18). doi: 10.1242/dev.200976. Epub 2022 Sep 27.
Retrotransposon Gag-like 5 [RTL5, also known as sushi-ichi-related retrotransposon homolog 8 (SIRH8)] and RTL6 (also known as SIRH3) are eutherian-specific genes presumably derived from a retrovirus and phylogenetically related to each other. They, respectively, encode a strongly acidic and extremely basic protein, and are well conserved among the eutherians. Here, we report that RTL5 and RTL6 are microglial genes with roles in the front line of innate brain immune response. Venus and mCherry knock-in mice exhibited expression of RTL5-mCherry and RTL6-Venus fusion proteins in microglia and appeared as extracellular dots and granules in the central nervous system. These proteins display a rapid response to pathogens such as lipopolysaccharide (LPS), double-stranded (ds) RNA analog and non-methylated CpG DNA, acting both cooperatively and/or independently. Experiments using Rtl6 or Rtl5 knockout mice provided additional evidence that RTL6 and RTL5 act as factors against LPS and dsRNA, respectively, in the brain, providing the first demonstration that retrovirus-derived genes play a role in the eutherian innate immune system. Finally, we propose a model emphasizing the importance of extra-embryonic tissues as the origin site of retrovirus-derived genes. This article has an associated 'The people behind the papers' interview.
逆转座子 gag 样蛋白 5 [RTL5，也称为 sushi-ichi 相关逆转座子同源物 8 (SIRH8)] 和 RTL6（也称为 SIRH3）是真兽类特有的基因，推测来源于逆转录病毒，彼此在系统发育上具有相关性。它们分别编码强酸性和极强碱性蛋白，在真兽类中高度保守。在这里，我们报告 RTL5 和 RTL6 是小胶质细胞基因，在先天脑免疫反应的前沿发挥作用。Venus 和 mCherry 敲入小鼠在小胶质细胞中表达 RTL5-mCherry 和 RTL6-Venus 融合蛋白，并在中枢神经系统中呈现出细胞外点和颗粒状。这些蛋白对病原体（如脂多糖（LPS）、双链（ds）RNA 类似物和非甲基化 CpG DNA）表现出快速反应，它们以协同和/或独立的方式发挥作用。使用 Rtl6 或 Rtl5 敲除小鼠的实验提供了额外的证据，表明 RTL6 和 RTL5 分别作为大脑中 LPS 和 dsRNA 的拮抗因子发挥作用，首次证明了逆转录病毒衍生基因在真兽类先天免疫系统中发挥作用。最后，我们提出了一个强调胚胎外组织作为逆转录病毒衍生基因起源位点的重要性的模型。本文有一个相关的“论文背后的人物”采访。
