Department of Cardiology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, 12200 Berlin, Germany.
German Center for Cardiovascular Research (DZHK), Site Berlin, 12200 Berlin, Germany.
Cells. 2022 Dec 8;11(24):3970. doi: 10.3390/cells11243970.
The evolutionary conserved gene cluster generates large noncoding transcripts remaining nuclear, while tRNA-like transcripts (mascRNA, menRNA) enzymatically generated from these precursors translocate to the cytosol. Whereas functions have been assigned to the nuclear transcripts, data on biological functions of the small cytosolic transcripts are sparse. We previously found and mice to display massive atherosclerosis and vascular inflammation. Here, employing selective targeted disruption of menRNA or mascRNA, we investigate the tRNA-like molecules as critical components of innate immunity. CRISPR-generated human ΔmascRNA and ΔmenRNA monocytes/macrophages display defective innate immune sensing, loss of cytokine control, imbalance of growth/angiogenic factor expression impacting upon angiogenesis, and altered cell-cell interaction systems. Antiviral response, foam cell formation/oxLDL uptake, and M1/M2 polarization are defective in ΔmascRNA/ΔmenRNA macrophages, defining first biological functions of menRNA and describing new functions of mascRNA. menRNA and mascRNA represent novel components of innate immunity arising from the noncoding genome. They appear as prototypes of a new class of noncoding RNAs distinct from others (miRNAs, siRNAs) by biosynthetic pathway and intracellular kinetics. Their region of origin appears as archetype of a functionally highly integrated RNA processing system.
进化保守的基因簇产生大量保持在核内的非编码转录本，而 tRNA 样转录本（mascRNA、menRNA）则从这些前体酶促生成并易位到细胞质。虽然已经为核转录本赋予了功能，但关于小细胞质转录本的生物学功能的数据仍然很少。我们之前发现 和 小鼠表现出大量的动脉粥样硬化和血管炎症。在这里，我们通过选择性靶向破坏 menRNA 或 mascRNA，研究了 tRNA 样分子作为先天免疫的关键组成部分。CRISPR 产生的人类 ΔmascRNA 和 ΔmenRNA 单核细胞/巨噬细胞显示出先天免疫感应缺陷、细胞因子控制丧失、生长/血管生成因子表达失衡，影响血管生成以及细胞间相互作用系统改变。ΔmascRNA/ΔmenRNA 巨噬细胞中的抗病毒反应、泡沫细胞形成/oxLDL 摄取和 M1/M2 极化受损，定义了 menRNA 的第一个生物学功能，并描述了 mascRNA 的新功能。menRNA 和 mascRNA 是先天免疫的新型非编码基因组来源的组成部分。它们通过生物合成途径和细胞内动力学与其他（miRNA、siRNA）不同，代表了一类新的非编码 RNA。它们的 区域起源似乎是功能高度整合的 RNA 加工系统的原型。
