Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA; Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
Mol Cell. 2024 Jun 6;84(11):2104-2118.e6. doi: 10.1016/j.molcel.2024.04.022. Epub 2024 May 17.
Circular RNAs (circRNAs) are stable RNAs present in cell-free RNA, which may comprise cellular debris and pathogen genomes. Here, we investigate the phenomenon and mechanism of cellular uptake and intracellular fate of exogenous circRNAs. Human myeloid cells and B cells selectively internalize extracellular circRNAs. Macrophage uptake of circRNA is rapid, energy dependent, and saturable. CircRNA uptake can lead to translation of encoded sequences and antigen presentation. The route of internalization influences immune activation after circRNA uptake, with distinct gene expression programs depending on the route of RNA delivery. Genome-scale CRISPR screens and chemical inhibitor studies nominate macrophage scavenger receptor MSR1, Toll-like receptors, and mTOR signaling as key regulators of receptor-mediated phagocytosis of circRNAs, a dominant pathway to internalize circRNAs in parallel to macropinocytosis. These results suggest that cell-free circRNA serves as an "eat me" signal and danger-associated molecular pattern, indicating orderly pathways of recognition and disposal.
环状 RNA（circRNAs）是存在于细胞外 RNA 中的稳定 RNA，可能包含细胞碎片和病原体基因组。在这里，我们研究了外源性 circRNAs 的细胞摄取和细胞内命运的现象和机制。人髓系细胞和 B 细胞选择性地摄取细胞外 circRNAs。circRNA 的摄取是快速的、能量依赖的和饱和的。circRNA 的摄取可以导致编码序列的翻译和抗原呈递。内化途径影响 circRNA 摄取后的免疫激活，根据 RNA 递送途径的不同，有不同的基因表达程序。全基因组 CRISPR 筛选和化学抑制剂研究将巨噬细胞清道夫受体 MSR1、Toll 样受体和 mTOR 信号作为受体介导的 circRNAs 吞噬作用的关键调节因子，这是一种将 circRNAs 与巨胞饮作用平行内化的主要途径。这些结果表明，细胞外 circRNA 作为一种“吃我”信号和危险相关分子模式，表明存在有序的识别和处理途径。
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