Copyright © 2012 Federation of European Biochemical Societies. Taken together, we propose that DOR exit from the nucleus is essential for basal autophagy stimulation even under nucleolus disruption. However, the nucleolus integrity is not essential for both DOR nucleo-cytoplasmic shuttling and DOR function on basal autophagy. Indeed, DOR already undergoes nucleo-cytoplasmic shuttling in basal conditions and, surprisingly, DOR exits continuously the nucleus and traverses the nucleolus. Our results show that DOR acts in basal autophagy. However, the mechanisms regulating basal autophagy still remain unknown. While autophagy has been mostly described as a stress-response mechanism, cells also need autophagy to maintain homeostasis in basal conditions. Mauvezin, Caroline Sancho, Ana Ivanova, Saska Palacin, Manuel Zorzano, AntonioĭOR is a bi-functional protein that regulates transcription and enhances starvation-induced autophagy. Nonetheless, we summarize the current knowledge of nucleos(t)ide synthesis inhibition-related innate immunity and propose it as a newly emerging antiviral mechanism of nucleoside analogs.ĭOR undergoes nucleo-cytoplasmic shuttling, which involves passage through the nucleolus. The precise crosstalk between these two independent processes remains to be determined. Intriguingly, a few recent reports have shown that some nucleoside analogs, including gemcitabine, activated innate immunity, inducing the expression of interferon-stimulated genes, through nucleos(t)ide synthesis inhibition. Nucleoside analogs generally interfere with cellular nucleos(t)ide synthesis pathways, resulting in the depletion or imbalance of (d)NTP pools. In recent years, gemcitabine, a cytidine analog in clinical use for the treatment of many solid tumors, was also shown to have antiviral activity against a broad range of viruses. Nucleoside analogs have been frequently identified as antiviral agents. Shin, Hye Jin Kim, Chonsaeng Cho, Sungchan Gemcitabine and Nucleos(t)ide Synthesis Inhibitors Are Broad-Spectrum Antiviral Drugs that Activate Innate Immunity.