Nuclear export signals and the fast track to the cytoplasm

One of the defining features of eukaryotic cells is the segregation of RNA biogenesis and DNA replication in the nucleus, separate from the cytoplasmic machinery for protein synthesis. Integration of the activities of the nucleus and cytoplasm requires the continuous transport of proteins, RNAs, and small molecules between these two compartments. Nucleocytoplasmic transport is mediated by nuclear pore complexes (NPCs), large supramolecular structures that span the nuclear envelope (reviewed by Rout and Wente, 1994). NPCs contain aqueous channels with a diameter of 10 nm, which allow ions, metabolites, and small proteins to diffuse passively between the nucleus and cytoplasm. Most proteins and RNAs are too large to cross the NPC by passive diffusion at physiologically relevant rates. Instead, they are transported through a gated transport channel in the NPC by active mechanisms, which are saturable and energy dependent and involve specific signals on the transported molecules (reviewed by Izaurralde and Mattaj, 1995; Melchior and Gerace, 1995). While substantial insight into the molecular basis for nuclear protein import has been obtained recently, nuclear export remains poorly understood. However, four papers in this issue of Cell (Wen et al., 1995; Fischer et al., 1995; Bogerd et al., 1995; Stutz et al., 1995) characterize molecular signals and their interacting components involved in the nuclear export of protein and RNA and herald a new period in the study of nuclear export mechanisms. Molecular Signals for Nuclear Import and Export A watershed for the analysis of nuclear protein import was the discovery that short amino acid stretches termed nuclear localization signals (N LSs) specify the nuclear import of many proteins. While N LSs lack a strict consensus, they are usually highly enriched in basic amino acids (reviewed by Dingwall and Laskey, 1991). NLSs containing both single and bipartite stretches of basic residues have been described (Figure 1), These N LSs can function when transplanted to nonnuclear proteins, either by inserting NLSspecifying codons into cDNAs or by coupling synthetic peptides containing NLSs to folded proteins. Characterization of nuclear export signals (NESs) has lagged considerably behind analysis of NLSs. This partly is due to the experimental difficulty of studying nuclear export, but also relates to the complex nature of many of the molecular species that are exported from the nucleus (discussed by Izaurralde and Mattaj, 1995). The RNA substrates for nuclear export are probably all transported as RNA-protein (RNP) complexes. Many or all of these RNPs contain multiple polypeptides, so it is difficult to know the precise composition of the substrate that is actually transMinireview