The RNA-Binding Protein SYNCRIP Is a Component of the Hepatocyte Exosomal Machinery Controlling MicroRNA Sorting

Santangelo, Laura; Giurato, Giorgio; Cicchini, Carla; Montaldo, Claudia; Mancone, Carmine; Tarallo, Roberta; Battistelli, Cecilia; Alonzi, Tonino; Weisz, Alessandro; Tripodi, Marco

doi:10.1016/j.celrep.2016.09.031

Cited by 451 publications

(439 citation statements)

References 47 publications

(63 reference statements)

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“…Our data support the hypothesis that long RNA export into EVs is a selective process and that RNA expression profiles from EVs do not simply reflect cellular RNA abundance (Kosaka et al, 2010; Santangelo et al, 2016; Skog et al, 2008; Squadrito et al, 2014; Valadi et al, 2007). Since original studies suggesting horizontal transfer of mRNAs and proteins (Ratajczak et al, 2006; Skog et al, 2008; Valadi et al, 2007), almost all known classes of RNA have been detected in extracellular fluids (Fritz et al, 2016).…”

Section: Discussionsupporting

confidence: 82%

“…However, the diversity of exRNA is extensive and microRNAs (miRNAs) are not the most abundant class of RNA found in EVs (Fritz et al, 2016; Mateescu et al, 2017). Analysis of cellular versus exRNA has repeatedly demonstrated selective biogenesis, export, and/or stability of specific RNAs (Cha et al, 2015; Dou et al, 2016; Kosaka et al, 2010; Santangelo et al, 2016; Skog et al, 2008; Squadrito et al, 2014; Valadi et al, 2007; Villarroya-Beltri et al, 2013; Wei et al, 2017). Elucidation of the mechanisms for selective sorting of cargo into EVs is critical to understanding extracellular signaling by RNA.…”

Section: Introductionmentioning

confidence: 99%

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Diverse Long RNAs Are Differentially Sorted into Extracellular Vesicles Secreted by Colorectal Cancer Cells

et al. 2018

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SUMMARY The regulation and functional roles of secreted coding and long noncoding RNAs (lncRNAs; >200 nt) are largely unknown. We previously showed that mutant KRAS colorectal cancer (CRC) cells release extracellular vesicles (EVs) containing distinct proteomes, microRNAs (miRNAs), and circular RNAs. Here, we comprehensively identify diverse classes of CRC extracellular long RNAs secreted in EVs and demonstrate differential export of specific RNAs. Distinct noncoding RNAs, including antisense transcripts and transcripts derived from pseudogenes, are enriched in EVs compared to cellular profiles. We detected strong enrichment of Rab13 in mutant KRAS EVs and demonstrate functional delivery of Rab13 mRNA to recipient cells. To assay functional transfer of lncRNAs, we implemented a CRISPR/ Cas9-based RNA-tracking system to monitor delivery to recipient cells. We show that gRNAs containing export signals from secreted RNAs can be transferred from donor to recipient cells. Our data support the existence of cellular mechanisms to selectively export diverse classes of RNA.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Diverse Long RNAs Are Differentially Sorted into Extracellular Vesicles Secreted by Colorectal Cancer Cells

et al. 2018

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“…To specifically delve into the role of miRNAs within exosomes a reagent where the production of miRNA-containing exosomes can be specifically blocked in vivo is needed. As we begin to identify factors involved in miRNA loading, such as Ybx1, hnRNPA2B1, and SYNCRIP (44–46), novel mouse strains can be created to address these questions. Furthermore, the production of exosomes containing only the miRNA of interest would make a strong tool both for further understanding of that miRNA within exosomes and for therapeutic applications down the road.…”

Section: Discussionmentioning

confidence: 99%

Rab27-Dependent Exosome Production Inhibits Chronic Inflammation and Enables Acute Responses to Inflammatory Stimuli

Alexander

Ramstead

Bauer

et al. 2017

The Journal of Immunology

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Extracellular vesicles, including exosomes, have recently been implicated as novel mediators of immune cell communication in mammals. However, roles for endogenously produced exosomes in regulating immune cell functions in vivo are just beginning to be identified. Here, we demonstrate that Rab27a and Rab27b double knockout (Rab27DKO) mice that are deficient in exosome secretion have a chronic, low-grade inflammatory phenotype characterized by elevated inflammatory cytokines and myeloproliferation. Upon further investigation, we found that some of these phenotypes could be complemented by WT hematopoietic cells or administration of exosomes produced by GM-CSF expanded bone marrow cells. Additionally, chronically inflamed Rab27DKO mice had a blunted response to bacterial LPS, resembling endotoxin tolerance. This defect was rescued by bone marrow exosomes from WT but not miR-155−/− cells suggesting that uptake of miR-155-containing exosomes is important for a proper LPS response. Further, we found that SHIP1 and IRAK-M, direct targets of miR-155 that are known negative regulators of the LPS response, were elevated in Rab27DKO mice and decreased following treatment with WT but not miR-155−/− exosomes. Together, our study finds that Rab27-dependent exosome production contributes to homeostasis within the hematopoietic system and appropriate responsiveness to inflammatory stimuli.

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“…54 Another RNA-binding protein, SYNCRIP, also functions as a key component of the hepatocyte exosomal miRNA sorting by directly binding to miRNAs sharing a short sequence called the hEXO motif. 55 In addition, there is a report that post-transcriptional modification of 3 0 end uridylation in miRNAs can direct exosomal miRNA sorting in B cells. 56 These findings indicate that specific motifs of miRNAs and their interacting proteins make the exosomes carry only certain miRNAs in their cargo, which suggests exosomal miRNAs may have dedicated tasks in the body.…”

Section: Evs and Small Rna Secretionmentioning

confidence: 99%

Tiny RNAs and their voyage via extracellular vesicles: Secretion of bacterial small RNA and eukaryotic microRNA

Choi

Cho

et al. 2017

Exp Biol Med (Maywood)

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MicroRNAs are small non-coding RNAs that bind to the 3′-untranslated region of target mRNAs and have transcriptional or translational inhibitory function in eukaryotes. Before microRNAs were widely known, bacterial non-coding small RNAs around 50–200 nt in length were discovered whose mechanism of action resembled that of microRNAs. Recently, RNAs that are of similar size to or smaller than microRNAs have been discovered in bacteria and indeed, this class of small RNAs have been found throughout all domains of life. Moreover, recent findings suggest that these tiny RNAs can be released via extracellular vesicles (such as exosomes in eukaryotes and outer membrane vesicles in bacteria), which in turn heralds a new field of research, interkingdom communication. This review discusses two similar classes of small RNAs in evolutionarily distinct eukaryotes and bacteria. In addition to their biogenesis and regulation, we discuss small RNA vehicles and their secretion. Impact statement The possible endogenous functions of small RNAs such as regulatory small RNAs in bacteria and microRNAs in eukaryotes have been extensively studied since they were first discovered. However, their powerful functions should not be seen as limited to their cells of origin. Recently, several papers have demonstrated that small RNAs function as signaling molecules between cells. This is possible because small RNAs can be shuttled around after being incorporated into environmentally protective extracellular vesicles. It is now clearly plausible that secreted small RNAs can regulate other types of cells through biofluids. Given their “common molecule” status, the role of small RNAs in mediating bacteria-human crosstalk is an emerging and competitive area of genetic research. This review provides insight into the function of small RNAs in intercellular and even interkingdom communication.

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The RNA-Binding Protein SYNCRIP Is a Component of the Hepatocyte Exosomal Machinery Controlling MicroRNA Sorting

Cited by 451 publications

References 47 publications

Diverse Long RNAs Are Differentially Sorted into Extracellular Vesicles Secreted by Colorectal Cancer Cells

Diverse Long RNAs Are Differentially Sorted into Extracellular Vesicles Secreted by Colorectal Cancer Cells

Rab27-Dependent Exosome Production Inhibits Chronic Inflammation and Enables Acute Responses to Inflammatory Stimuli

Tiny RNAs and their voyage via extracellular vesicles: Secretion of bacterial small RNA and eukaryotic microRNA

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