More than a zip code: global modulation of cellular function by nuclear localization signals

Extensive structural and functional studies have been carried out in the field of nucleocytoplasmic transport. Nuclear transport factors, such as Importin-α/-β, recognize nuclear localization signals (NLSs) on cargo, and together with the small GTPase Ran, facilitate their nuclear localization. However, it is now emerging that binding of nuclear transport factors to NLSs not only mediates nuclear transport but also contributes to a variety of cellular functions in eukaryotes. Here, we describe recent advances that reveal how NLSs facilitate diverse cellular functions beyond nuclear transport activity. We review separately NLS-mediated regulatory mechanisms at different levels of biological organization, including (a) assembly of higher-order structures; (b) cellular organelle dynamics; and (c) modulation of cellular stress responses and viral infections. Finally, we provide mechanistic insights into how NLSs can regulate such a broad range of functions via their structural and biochemical properties.