Y-box protein 1 is required to sort microRNAs into exosomes in cells and in a cell-free reaction

Shurtleff, Matthew J.; Karfilis, Kate V.; Temoche-Diaz, Morayma M.; Ri, Sayaka; Schekman, Randy

doi:10.1101/040238

Cited by 18 publications

(33 citation statements)

References 65 publications

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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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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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“…Some RBPs can guide transport to specific cellular areas, and – as has been recently shown in animal cells – facilitate RNA export from cells and over long distances (Hematy et al ., ; Shurtleff et al ., ). Concerning long‐distance mobility of RNAs in plants, the co‐occurrence of different RNAs and several RBPs in phloem samples suggests their involvement in conferring RNA stability and mobility.…”

Section: Mode Of Rna Transportmentioning

confidence: 97%

Long distance RNA movement

Kehr¹,

2018

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Contents Summary29I.Introduction29II.Phloem as a conduit for macromolecules30III.Classes of phloem transported RNAs and their function32IV.Mode of RNA transport35V.Conclusions37Acknowledgements37References37 Summary In higher plants, small noncoding RNAs and large messenger RNA (mRNA) molecules are transported between cells and over long distances via the phloem. These large macromolecules are thought to get access to the sugar‐conducting phloem vessels via specialized plasmodesmata (PD). Analyses of the phloem exudate suggest that all classes of RNA molecules, including silencing‐induced RNAs (siRNAs), micro RNAs (miRNAs), transfer RNAs (tRNAs), ribosomal RNA (rRNAs) and mRNAs, are transported via the vasculature to distant tissues. Although the functions of mobile siRNAs and miRNAs as signalling molecules are well established, we lack a profound understanding of mobile mRNA function(s) in recipient cells and tissues, and how they are selected for transport. A surprisingly high number of up to thousands of mRNAs were described in diverse plant species such as cucumber, pumpkin, Arabidopsis and grapevine to move long distances over graft junctions to distinct body parts. In this review, we present an overview of the classes of mobile RNAs, the potential mechanisms facilitating RNA long‐distance transport, and the roles of mobile RNAs in regulating transcription and translation. Furthermore, we address potential function(s) of mobile protein‐encoding mRNAs with respect to their characteristics and evolutionary constraints.

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“…A second study reported that, alternatively, tRFs might function in analogy to miRNAs, i.e., by binding to the 3 ′ UTR of mRNAs, inhibiting the expression of RPA1 mRNA (Maute et al 2013). Recent reports imply that YBX1 is required for loading of various RNA species, including tRFs, into exosomes (Shurtleff et al 2016). Some studies have reported that YBX1 binds to several RNAs like tRNA fragments and miRNAs (Blenkiron et al 2013;Goodarzi et al 2015;Liu et al 2015).…”

Section: Leumentioning

confidence: 99%

Identification of urinary exosomal noncoding RNAs as novel biomarkers in chronic kidney disease

Khurana

Ranches

Schafferer

et al. 2016

RNA

115

117

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In chronic kidney disease (CKD), the decline in the glomerular filtration rate is associated with increased morbidity and mortality and thus poses a major challenge for healthcare systems. While the contribution of tissue-derived miRNAs and mRNAs to CKD progression has been extensively studied, little is known about the role of urinary exosomes and their association with CKD. Exosomes are small, membrane-derived endocytic vesicles that contribute to cell-to-cell communication and are present in various body fluids, such as blood or urine. Next-generation sequencing approaches have revealed that exosomes are enriched in noncoding RNAs and thus exhibit great potential for sensitive nucleic acid biomarkers in various human diseases. Therefore, in this study we aimed to identify urinary exosomal ncRNAs as novel biomarkers for diagnosis of CKD. Since up to now most approaches have focused on the class of miRNAs, we extended our analysis to several other noncoding RNA classes, such as tRNAs, tRNA fragments (tRFs), mitochondrial tRNAs, or lincRNAs. For their computational identification from RNA-seq data, we developed a novel computational pipeline, designated as ncRNASeqScan. By these analyses, in CKD patients we identified 30 differentially expressed ncRNAs, derived from urinary exosomes, as suitable biomarkers for early diagnosis. Thereby, miRNA-181a appeared as the most robust and stable potential biomarker, being significantly decreased by about 200-fold in exosomes of CKD patients compared to healthy controls. Using a cell culture system for CKD indicated that urinary exosomes might indeed originate from renal proximal tubular epithelial cells.

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Y-box protein 1 is required to sort microRNAs into exosomes in cells and in a cell-free reaction

Cited by 18 publications

References 65 publications

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

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

Long distance RNA movement

Identification of urinary exosomal noncoding RNAs as novel biomarkers in chronic kidney disease

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