Background: Small nucleolar RNAs (snoRNAs) are thought to be exclusively nuclear. Results: Doxorubicin stress results in significant accumulation of cytosolic snoRNAs via a pathway involving Nox4D and superoxide. Conclusion: snoRNAs are present in the cytoplasm, and their cytosolic abundance is dynamically regulated. Significance: Previously unexplained snoRNA biology may be the result of snoRNA interactions with cytoplasmic targets.

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.