Transportin‐1 and Transportin‐2: Protein nuclear import and beyond

Abstract

Edited by Ulrike KutayKeywords: Transportin Importins Karyopherins Nuclear import Nucleo-cytoplasmic transport NLS Kap104p Transportin-1 Transportin-2 Karyopherin-b2 hnRNP A1 FUS a b s t r a c t Nearly 20 years after its identification as a new b-karyopherin mediating the nuclear import of the RNA-binding protein hnRNP A1, Transportin-1 is still commonly overlooked in comparison with its best known cousin, Importin-b. Transportin-1 is nonetheless a considerable player in nucleo-cytoplasmic transport. Over the past few years, significant progress has been made in the characterization of the nuclear localization signals (NLSs) that Transportin-1 recognizes, thereby providing the molecular basis of its diversified repertoire of cargoes. The recent discovery that mutations in the Transportin-dependent NLS of FUS cause mislocalization of this protein and result in amyotrophic lateral sclerosis illustrates the importance of Transportin-dependent import for human health. Besides, new functions of Transportin-1 are emerging in processes other than nuclear import. Here, we summarize what is known about Transportin-1 and the related b-karyopherin Transportin-2. Ó 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. Basis of protein nucleo-cytoplasmic transportActive nucleo-cytoplasmic transport of proteins is mostly carried out by b-karyopherins, a family of factors functionally divided into importins and exportins. Importins bind to the nuclear localization signal (NLS) of their cargoes in the cytoplasm, either directly or through an adaptor. The importin/cargo complexes cross the nuclear pore complex (NPC) through the interactions of the importin with nucleoporins. In the nucleus, importins are bound by Ran-GTP, which releases the cargo. Importins are then recycled to the cytoplasm in association with Ran-GTP. On the cytoplasmic face of the NPC, Ran hydrolyzes its bound GTP into GDP and dissociates, freeing the importin for a new import cycle (see for example [1] for review). Exportins work in a similar way but in reverse. In the nucleus, exportins cooperatively bind Ran-GTP and a cargo featuring a fitting nuclear export signal (NES). Once the trimeric complexes reach the cytoplasm, they are dissociated and free exportins return to the nucleus to complete the cycle (see for example [2] for review). Thus, while Ran-GTP binding causes importins to release their cargoes, it is required for exportins to bind theirs. Neither importins nor exportins have significant binding affinity for the GDP-bound form of Ran. Therefore, the directionality of the transfers is maintained by mechanisms that ensure that nuclear Ran is bound to GTP and cytoplasmic Ran to GDP. The nuclear part of this task is carried out by the chromatin-associated guanine exchange factor RCC1, which promotes the exchange of GDP for GTP on nuclear Ran. Three factors located on the cytosolic face of the NPC (RanBP1, RanBP2, and RanGAP) collaborate to ensure the hydrolysis of Ran-bound GTP by Ran as soon as it goes ou...

Multiple exportins influence thyroid hormone receptor localization

“…2B). Originally proposed to mediate bidirectional transport, more recent studies maintain that transportins 1 and 2 are restricted to mediating nuclear import of RNA-binding proteins that function as splicing regulators (Twyffels et al, 2014). Therefore, we predicted that the transportins would not be involved in TRα1 shuttling.…”

Landscape of nuclear transport receptor cargo specificity

“…However, several technical obstacles have rendered the systematic mapping of cargo–NTR relationships challenging: (i) The transient nature of cargo–NTR interactions makes them largely inaccessible to biochemical identification by NTR‐centric affinity purification; (ii) each NTR does recognize a multitude of cargos and their cargo spectrum might overlap; and (iii) cargo abundances (copy numbers per cell) span several orders of magnitude in situ . The vast majority of previous studies therefore were designed in a cargo‐centric manner and have reported transport pathways for individual cargos (for review, see, e.g., Chook & Süel, 2011; Kimura & Imamoto, 2014; Twyffels et al , 2014). Although powerful for studying the contribution of the nuclear transport system to individual cellular mechanisms, these approaches are not suitable to comprehensively chart its cargo spectrum.…”

IPO3-mediated Nonclassical Nuclear Import of NF-κB Essential Modulator (NEMO) Drives DNA Damage-dependent NF-κB Activation

“…Thus, the differences in the critical HEAT repeats between IPO3 and TRN1 could be responsible for the differential interaction with NEMO. Whereas well established cargos for TRN1 and IPO3 are involved in RNA metabolism (48), NEMO represents a unique cargo of IPO3 in a non-RNA processing pathway, thereby identifying genotoxic stress-induced NF-B signaling as an important biological pathway regulated by IPO3, not shared by TRN1.…”

“…For example, co-crystal structure analysis demonstrated that TRN1 (transportin 1, TNPO1, IPO2) makes extensive contacts with nonclassical NLS sequences known as the proline-tyrosine-NLS (PY-NLS) spanning 30 -40 amino acids via its HEAT repeat motifs (46,47). The sequence model suggested that the PY-NLS motif is present in potentially over 80 distinct proteins (47,48). TRN1 also recognizes cargos that do not have PY-NLS motifs (48), further diversifying the number of substrates it can recognize.…”

“…The sequence model suggested that the PY-NLS motif is present in potentially over 80 distinct proteins (47,48). TRN1 also recognizes cargos that do not have PY-NLS motifs (48), further diversifying the number of substrates it can recognize. In addition, a recent study identified an importin-independent pathway mediated by direct binding of some ankyrin repeat-containing proteins to Ran-GDP and NTF2 (nuclear transport factor 2) (49).…”