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1.
Mol Cell ; 84(11): 2104-2118.e6, 2024 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-38761795

RESUMEN

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.


Asunto(s)
Macrófagos , Fagocitosis , ARN Circular , Transducción de Señal , ARN Circular/genética , ARN Circular/metabolismo , Humanos , Macrófagos/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/genética , Animales , Receptores Toll-Like/metabolismo , Receptores Toll-Like/genética , Linfocitos B/metabolismo , Linfocitos B/inmunología , Receptores Depuradores de Clase A/metabolismo , Receptores Depuradores de Clase A/genética , Presentación de Antígeno , Pinocitosis , Ratones
2.
Nat Cell Biol ; 24(7): 1129-1140, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35739318

RESUMEN

RNA-mediated interference (RNAi) is a conserved mechanism that uses small RNAs (sRNAs) to silence gene expression. In the Caenorhabditis elegans germline, transcripts targeted by sRNAs are used as templates for sRNA amplification to propagate silencing into the next generation. Here we show that RNAi leads to heritable changes in the distribution of nascent and mature transcripts that correlate with two parallel sRNA amplification loops. The first loop, dependent on the nuclear Argonaute HRDE-1, targets nascent transcripts and reduces but does not eliminate productive transcription at the locus. The second loop, dependent on the conserved helicase ZNFX-1, targets mature transcripts and concentrates them in perinuclear condensates. ZNFX-1 interacts with sRNA-targeted transcripts that have acquired poly(UG) tails and is required to sustain pUGylation and robust sRNA amplification in the inheriting generation. By maintaining a pool of transcripts for amplification, ZNFX-1 prevents premature extinction of the RNAi response and extends silencing into the next generation.


Asunto(s)
Proteínas de Caenorhabditis elegans , Animales , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , ADN Helicasas/genética , Células Germinativas/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo
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