Nuclear export factor 3 regulates localization of small nucleolar RNAs

Abstract

Small nucleolar RNAs (snoRNAs) guide chemical modifications of ribosomal and small nuclear RNAs, functions that are carried out in the nucleus. Although most snoRNAs reside in the nucleolus, a growing body of evidence indicates that snoRNAs are also present in the cytoplasm and that snoRNAs move between the nucleus and cytoplasm by a mechanism that is regulated by lipotoxic and oxidative stress. Here, in a genome-wide shRNA-based screen, we identified nuclear export factor 3 (NXF3) as a transporter that alters the nucleocytoplasmic distribution of box C/D snoRNAs from the ribosomal protein L13a () locus. Using RNA-sequencing analysis, we show that NXF3 associates not only with snoRNAs, but also with a broad range of box C/D and box H/ACA snoRNAs. Under homeostatic conditions, gain- or loss-of-function of NXF3, but not related family member NXF1, decreases or increases cytosolic snoRNAs, respectively. Furthermore, treatment with the adenylyl cyclase activator forskolin diminishes cytosolic localization of the snoRNAs through a mechanism that is dependent on NXF3 but not NXF1. Our results provide evidence of a new role for NXF3 in regulating the distribution of snoRNAs between the nuclear and cytoplasmic compartments.

Death by lipids: The role of small nucleolar RNAs in metabolic stress

“…Phenotype-driven forward genetic screens have advanced our understanding of the regulation of cellular responses to lipid overload in mammalian cells. Such approaches rely on random disruption of genetic loci or knockdown, followed by positive selection of cells that survive better under lipotoxic conditions or by negative selection of cells that have enhanced sensitivity to lipotoxicity (24,35,42,43). Genetic disruptions achieved by short hairpin RNA, siRNA, and CRISPR are typically designed to target open reading frames.…”

“…In these cells, levels of all mature intronic snoRNAs are decreased, even though splicing to produce mRNAs remains unperturbed. Second, short hairpin RNA-mediated targeting of nuclear export factor 3 (NXF3) also renders cells resistant to lipotoxic stress (42). The vast majority of snoRNAs are localized to the nucleolus, and lipotoxic stress increases the appearance of snoRNAs in the cytoplasm (54).…”

The Unforeseen Non-Coding RNAs in Head and Neck Cancer

“…snoRNAs are a type of linear transcripts with protein-guiding function. Depending on their sequence characteristics, the snoRNAs are divided into C/D snoRNA, H/ACA snoRNA, and U snoRNA [ 116 , 117 ]. The C/D snoRNA and the H/ACA snoRNA are transcribed from protein-coding genes, as primary mRNAs.…”

“…Then the 3’ and the 5’ end are shortened by the local endonucleases, until the mature C/D or H/ACA snoRNA is generated. The U3, U8 and U13 snoRNAs are transcribed from the promoter regions of RNA Pol II [ 116 ].…”

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

“…This redistribution of snoRNAs depends on superoxide and NADPH oxidase activity and does not simply result from compromise of the nuclear compartment. We also recently found that nuclear export factor 3 (NXF3) regulates the trafficking of snoRNAs between the nucleus and cytosol (11). Importantly, regulated appearance of snoRNAs in the cytoplasm raises the possibility of novel functions for snoRNAs outside the nucleus.…”