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Nuclear export factor 3 regulates localization of snoRNAs

Small nucleolar RNAs (snoRNAs) guide chemical modifications of ribosomal and small nuclear RNAs and canonically localize in the nucleus. Recent studies have demonstrated that some snoRNAs have broader cellular roles, such as a function for ribosomal protein L13a (Rpl13a) snoRNAs in lipotoxic and oxidative stress responses. The observation that these and other snoRNAs are present in the cytoplasm under homeostatic conditions and accumulate in the cytosol during metabolic stress suggests that localization of snoRNAs is tightly regulated. However, there is no known nucleocytoplasmic transporter for snoRNAs. Using an shRNA loss‐of‐function genetic screen in endothelial cells, we found that an shRNA targeting nuclear export factor 3 (NXF3), a member of the nuclear RNA export factor family, caused resistance to metabolic stress. Given that Rpl13a snoRNAs are critical for metabolic stress‐induced cell death, and that these snoRNAs accumulate in the cytoplasm under metabolic stress conditions, we hypothesized that NXF3 may function as a regulator of snoRNA distribution. In transient transfection assays, NXF3 knockdown increased abundance of cytosolic Rpl13a snoRNAs, whereas NXF3 overexpression led to decreased cytosolic levels, suggesting that NXF3 functions in nuclear import of snoRNAs. We found the Rpl13a snoRNAs co‐immunoprecipitated with NXF3, consistent with a role for NXF3 as a snoRNA transporter. Treatment of cells with forskolin, which causes a rapid decrease in cytosolic snoRNAs, increased both nuclear localization of NXF3 and association of NXF3 with Rpl13a snoRNAs. Treatment of cells with doxorubicin, which causes cytosolic accumulation of Rpl13a snoRNAs, decreased association of the snoRNAs with NXF3. Together, our findings suggest a model in distribution of snoRNAs between the nuclear and cytoplasmic compartments that is regulated by NXF3.