Long-range function of secreted small nucleolar RNAs that direct 2′-O-methylation

• Published in: The Journal of biological chemistry Vol. 293; no. 34; pp. 13284 - 13296
• Main Authors: Rimer, Jamie M., Lee, Jiyeon, Holley, Christopher L., Crowder, Robert J., Chen, Delphine L., Hanson, Phyllis I., Ory, Daniel S., Schaffer, Jean E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.08.2018; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Biological Transport; Cell Nucleolus - genetics; Cell Nucleolus - metabolism; Cell Nucleus - genetics; Cell Nucleus - metabolism; exosome (vesicle); Female; Humans; inflammation; Male; Methylation; Mice; Mice, Knockout; Ribosomal Proteins - physiology; RNA; RNA methylation; RNA Processing, Post-Transcriptional; RNA, Ribosomal - chemistry; RNA, Ribosomal - metabolism; RNA, Small Nucleolar - genetics; RNA, Small Nucleolar - metabolism; secretion; small nucleolar RNA (snoRNA); exosome (vesicle); secretion; inflammation; small nucleolar RNA (snoRNA); RNA methylation
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.RA118.003410

Small nucleolar RNAs (snoRNAs) are noncoding RNAs that guide chemical modifications of structural RNAs. Whereas snoRNAs primarily localize in the nucleolus, where their canonical function is to target nascent ribosomal RNAs for 2′-O-methylation, recent studies provide evidence that snoRNAs traffic out of the nucleus. Furthermore, RNA-Seq data indicate that extracellular vesicles released from cells contain snoRNAs. However, it is not known whether snoRNA secretion is regulated or whether secreted snoRNAs are functional. Here, we show that inflammation stimulates secretion of Rpl13a snoRNAs U32a (SNORD32a), U33 (SNORD33), U34 (SNORD34), and U35a (SNORD35a) from cultured macrophages, in mice, and in human subjects. Secreted snoRNAs co-fractionate with extracellular vesicles and are taken up by recipient cells. In a murine parabiosis model, we demonstrate that snoRNAs travel through the circulation to function in distant tissues. These findings support a previously unappreciated link between inflammation and snoRNA secretion in mice and humans and uncover a potential role for secreted snoRNAs in cell–cell communication.