Cell contact-dependent acquisition of cellular and viral nonautonomously encoded small RNAs

Rechavi, Oded; Erlich, Yaniv; Amram, Hila; Flomenblit, Lena; Karginov, Fedor V.; Goldstein, Itamar; Hannon, Gregory J.; Kloog, Yoel

doi:10.1101/gad.1789609

Cited by 110 publications

(112 citation statements)

References 33 publications

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“…Previous studies showed the presence of cellular miRNAs in vesicles isolated from human peripheral blood (5-7). Taken together these data are consistent with the notion of functional miRNA transfer through exosomes as a possible mechanism of intercellular communication and immune regulation (34), although alternative methods of transfer cannot be ruled out (8,35).…”

Section: Discussionsupporting

confidence: 77%

Functional delivery of viral miRNAs via exosomes

Pegtel

Cosmopoulos

Thorley‐Lawson

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

1,461

1,227

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Noncoding regulatory microRNAs (miRNAs) of cellular and viral origin control gene expression by repressing the translation of mRNAs into protein. Interestingly, miRNAs are secreted actively through small vesicles called "exosomes" that protect them from degradation by RNases, suggesting that these miRNAs may function outside the cell in which they were produced. Here we demonstrate that miRNAs secreted by EBV-infected cells are transferred to and act in uninfected recipient cells. Using a quantitative RT-PCR approach, we demonstrate that mature EBV-encoded miRNAs are secreted by EBV-infected B cells through exosomes. These EBV-miRNAs are functional because internalization of exosomes by MoDC results in a dose-dependent, miRNAmediated repression of confirmed EBV target genes, including CXCL11/ ITAC, an immunoregulatory gene down-regulated in primary EBVassociated lymphomas. We demonstrate that throughout coculture of EBV-infected B cells EBV-miRNAs accumulate in noninfected neighboring MoDC and show that this accumulation is mediated by transfer of exosomes. Thus, the exogenous EBV-miRNAs transferred through exosomes are delivered to subcellular sites of gene repression in recipient cells. Finally, we show in peripheral blood mononuclear cells from patients with increased EBV load that, although EBV DNA is restricted to the circulating B-cell population, EBV BART miRNAs are present in both B-cell and non-B-cell fractions, suggestive of miRNA transfer. Taken together our findings are consistent with miRNA-mediated gene silencing as a potential mechanism of intercellular communication between cells of the immune system that may be exploited by the persistent human γ-herpesvirus EBV.

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Section: Discussionsupporting

confidence: 77%

Functional delivery of viral miRNAs via exosomes

Pegtel

Cosmopoulos

Thorley‐Lawson

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

1,461

1,227

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“…Zernecke et al (9) showed that the transfer of miR-126 loaded into endothelial apoptotic bodies induced the expression of CXCL12 and the recruitment of progenitor cells, thereby alleviating atherosclerosis. Additionally, Rechavi et al (8) proposed that viruses could tamper with the host immune response by transportation of viral non-autonomously encoded small RNAs. Both vascular protection and manipulation of the immune system by viruses occur for a long term.…”

Section: Discussionmentioning

confidence: 99%

Secretory Mechanisms and Intercellular Transfer of MicroRNAs in Living Cells

Kosaka¹,

Iguchi

Yoshioka³

et al. 2010

Journal of Biological Chemistry

1,751

1,482

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The existence of circulating microRNAs (miRNAs) in the blood of cancer patients has raised the possibility that miRNAs may serve as a novel diagnostic marker. However, the secretory mechanism and biological function of extracellular miRNAs remain unclear. Here, we show that miRNAs are released through a ceramide-dependent secretory machinery and that the secretory miRNAs are transferable and functional in the recipient cells. Ceramide, whose biosynthesis is regulated by neutral sphingomyelinase 2 (nSMase2), triggers secretion of small membrane vesicles called exosomes. The decreased activity of nSMase2 with a chemical inhibitor, GW4869, and a specific small interfering RNA resulted in the reduced secretion of miRNAs. Complementarily, overexpression of nSMase2 increased extracellular amounts of miRNAs. We also revealed that the endosomal sorting complex required for transport system is unnecessary for the release of miRNAs. Furthermore, a tumorsuppressive miRNA secreted via this pathway was transported between cells and exerted gene silencing in the recipient cells, thereby leading to cell growth inhibition. Our findings shed a ray of light on the physiological relevance of secretory miRNAs.It has been well known that extracellular RNAs circulate in the blood of healthy people and diseased patients with sufficient integrity, although ribonuclease is present in both plasma and serum (1). The spectrum of RNAs whose presence was demonstrated in plasma and other body fluids, such as urine and breast milk, extends from housekeeping genes to fetal genes detected in pregnant women and genes overexpressed in a variety of different tumors (2). To explain the stability of circulating RNAs, it was suggested that extracellular RNAs are included within lipoprotein vesicles. Indeed, exogenous RNAs added to plasma or blood are immediately degraded, whereas endogenous plasma RNAs are stable for hours under the same conditions (3). Moreover, the treatment of some detergents results in immediate degradation of plasma extracellular RNAs, apparently due to disruption of the lipid vesicles. These findings clearly indicate that extracellular RNAs are packaged in some kinds of secretory particles including apoptotic bodies and exosomes, and thus, they are protected from dominantly existing ribonucleases.Apoptotic bodies are small membranous particles released during programmed cell death (4), and exosomes are small intraluminal vesicles (50 -100 nm in diameter) of multivesicular bodies (MVB) 3 released on exocytic fusion of MVB with plasma membranes (5). Currently, accumulating evidence suggests that these secretory vesicles can function as intercellular transmitters to convey their contents, in particular, microRNA (miRNA) (6 -8). Recent studies reported that extracellular exosomal miRNAs were transferred into other cells and that apoptotic bodies delivered miR-126 into endothelial cells (9). Despite these advances, however, the underlying mechanism of the secretory process and the biological function of circulating miRNAs are not yet...

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Section: Rna-mediated Gene Silencing and Inheritancementioning

confidence: 94%

“…This observation challenges an important principle in evolutionary biology known as the "Weismann Barrier" (also termed "The second law of biology"), according to which genetic information cannot pass from the soma to the germline [13]. Recently it was demonstrated that higher organisms also use RNAi to silence genes in a non-cell autonomous manner [14,15], suggesting that soma-germline RNA-mediated communication could be widely conserved.While in most cases wild-type gene activity is restored to baseline after dsRNA exposure in the second generation, targeting certain genes can result in lasting interference [16]. Several factors influence the persistency of RNAi inheritance, and segregation of the effect does not follow Mendel's rules of heredity -I will now briefly describe the dynamics of this unusual genetic process.…”

mentioning

confidence: 94%

Guest list or black list: heritable small RNAs as immunogenic memories

Rechavi

2014

Trends in Cell Biology

Self Cite

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Small RNA-mediated gene silencing plays a pivotal role in genome immunity by recognizing and eliminating viruses and transposons which otherwise may colonize the genome. However, this can be challenging since individual genomic parasites are highly diverse, and employ multiple immune evasion techniques. In this review, I discuss a new theory proposing that the integrity of the germline is maintained by transgenerationally-transmitted RNA "memories" that record ancestral gene expression patterns, and delineate "Self" from "Foreign" sequences. To maintain such recollection two tactics are employed in parallel: "black listing" of invading nucleic acids, and "guest listing" of endogenous genes. Studies in a number of organisms have shown that this memorization is used by the next generation small RNAs to act as "Inherited Vaccines" that ambush invading elements, or as "Inherited Licenses" that grant the transcription of autogenous sequences. KeywordsSmall RNA; Transgenerational Inheritance; Inherited Immunity; Self Vs. Non-Self; "Inherited Vaccines" Overview of transgenerational inheritanceEvolution progresses through an interplay between two major forces, selection and variation. Since the formulation of the Modern Synthesis the theory holds that the environment is limited in its contribution to the evolutionary course of action -it affects selection, but not the degree of variation [1,2]. However, recent discoveries in epigenetics suggest that the environment may influence variability as well [1]. If the parental environment is predictive of the conditions that the progeny will face (often for sessile or short-lived organisms), epigenetic responses can change the output of the encoded genetic information in an adaptive manner [3]. For example, the water flea Daphnia changes its normal developmental course and develops a "helmet" that protects it from predators, if it is born to a mother that survived a similar attack [4].Correspondence to: odedrechavi@gmail.com. Over the years, controversy surrounded the study of environmentally affected transgenerational inheritance. Today, an improved understanding of epigenetic mechanisms at the molecular level has provided a logical background to explain how, heretically, an adaptive acquired trait could become heritable [5]. Several epigenetic mechanisms could regulate the expression of relevant genes during transgenerational inheritance including DNA methylation, histone modification, and transmission of regulatory RNAs. Moreover, in many organisms, these pathways appear to be interconnected [5][6][7][8]. Europe PMC Funders GroupThis review will concentrate on recent discoveries that establish a role for small RNAs in transgenerational transmission of acquired defense. Furthermore, exciting examples of RNA-mediated non-Mendelian genetic effects will be discussed, along with their possible implications for the study of evolution and immunology. RNA-mediated gene silencing and inheritanceSince the original discovery that small RNAs derived from exogenously-provided dou...

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Cell contact-dependent acquisition of cellular and viral nonautonomously encoded small RNAs

Abstract: In some organisms, small RNA pathways can act nonautonomously, with responses spreading from cell to cell.

Cited by 110 publications

References 33 publications

Functional delivery of viral miRNAs via exosomes

Functional delivery of viral miRNAs via exosomes

Secretory Mechanisms and Intercellular Transfer of MicroRNAs in Living Cells

Guest list or black list: heritable small RNAs as immunogenic memories

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