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Abstract
Many RNA-binding proteins (RBPs) dynamically shuttle between the nucleus and the cytoplasm, often exerting different functions in each compartment. Therefore, the nucleo-cytoplasmic distribution of RBPs has a strong impact on their activity. Here we describe the localization and the shuttling properties of the tandem zinc finger RBP dTIS11, which is the Drosophila homolog of mammalian TIS11 proteins. Drosophila and mammalian TIS11 proteins act as destabilizing factors in ARE-mediated decay. At equilibrium, dTIS11 is concentrated mainly in the cytoplasm. We show that dTIS11 is a nucleo-cytoplasmic shuttling protein whose nuclear export is mediated by the exportin CRM1 through the recognition of a nuclear export signal (NES) located in a different region comparatively to its mammalian homologs. We also identify a cryptic Transportin-dependent PY nuclear localization signal (PY-NLS) in the tandem zinc finger region of dTIS11 and show that it is conserved across the TIS11 protein family. This NLS partially overlaps the second zinc finger ZnF2. Importantly, mutations disrupting the capacity of the ZnF2 to coordinate a Zinc ion unmask dTIS11 and TTP NLS and promote nuclear import. All together, our results indicate that the nuclear export of TIS11 proteins is mediated by CRM1 through diverging NESs, while their nuclear import mechanism may rely on a highly conserved PY-NLS whose activity is negatively regulated by ZnF2 folding.
Highlights
The nucleo-cytoplasmic compartmentalization enables eukaryotic cells to develop sophisticated mechanisms to regulate gene expression at post-transcriptional levels
Upon treatment of the cells with leptomycin B (LMB), an inhibitor of the CRM1 exportin [23,24], it is partially redistributed into the nucleus (Fig. 1C)
This result suggests that dTIS11, mainly cytoplasmic at steady state, is a nucleocytoplasmic shuttling protein whose nuclear export is mediated by a CRM1-dependent pathway
Summary
The nucleo-cytoplasmic compartmentalization enables eukaryotic cells to develop sophisticated mechanisms to regulate gene expression at post-transcriptional levels. Messenger RNAs undergo several maturation processes in the nucleus before being exported to the cytoplasm, where they are dispatched to specialized machineries that translate and degrade them All these processes are mediated by RNA-binding proteins (RBPs), many of which are able to shuttle between the nucleus and the cytoplasm. Nucleo-cytoplasmic traffic occurs through the nuclear pore complexes (NPCs) These large structures that span the nuclear envelope provide a diffusion channel for small molecules and enable active transport of molecules ranging from single proteins to ribosomal subunits and mRNA export complexes. Active transport of proteins is mediated by receptors belonging to the karyopherin b family, which includes about twenty members in mammals [3] These factors recognize nuclear localization signals (NLS) or nuclear export signals (NES) in their protein cargoes and convey them through the NPC. The directionality of the transport here relies on the remodeling of the mRNP on the cytoplasmic side of the NPC [8]
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