TABLE 1.
Target factors of NIRs in non-import processes.
| NIR | NIR cargo/ targeted process | NIR-interacting localisation signal(s) in cargo | NIR functions | Reference |
|---|---|---|---|---|
| Mitotic completion a | ||||
| Importin beta-1 | HURP | NLS | Importin beta-1 binding prevents the release of HURP at its site of action (i.e. microtubule growing ends) and its premature interaction with APC/C. | Silljé et al. (2006), Song and Rape (2010), Song et al. (2014) |
| Importin beta-1 | NuSAP1 | NLS | Importin beta-1 binding prevents NUSAP1 function in formation of microtubule asters and its premature interaction with APC/C. | Ribbeck et al. (2006), Song and Rape (2010) |
| Importin beta-1 | BUB3/BuGZ | NLS | Importin beta-1 prevents the premature interaction of BUB3/BuGZ with Ubr5. | Jiang et al. (2015) |
| Importin beta-1 | RepoMan | NLS | RepoMan/importin beta-1 complex localizes to the chromosome periphery at mitotic exit to initiate NE reassembly. | Vagnarelli et al. (2011) |
| Importin beta-1 | PP2A/R1A/B55alpha | NLS | Importin beta-1 and PP2A co-purify and their co-depletion synergistically delays mitotic exit. | Schmitz et al. (2010) |
| Ciliogenesis and ciliary transport | ||||
| Importin beta-1 | Crumbs3 (CRB3) alternative splicing product (CRB3-CLPI) | Direct interaction, region of interaction not identified | Importin beta-1 is necessary for CRB3-CLPI ciliary targeting. Expression of dominant-negative importin beta-1 phenocopies the effects of CRB3-CLPI knockdown (loss of cilia, centrosomal and spindle abnormalities). | Fan et al. (2007) |
| TNPO1 | RP2 to ciliary basis | NLS and M9 | TNPO1 inactivation abolishes RP2 ciliary entry; pathogenetic mutations in RP2 fall in the M9 signal, blocking RP2 interaction with and ciliary delivery by TNPO1. | Hurd et al. (2011) |
| TNPO1 | Fibrocystin, photoreceptor retinol dehydrogenase, rhodopsin, RP2 | CLS | TNPO1 interacts with CLSs in ciliary membrane residents; complexes are regulated by GTPase Rab8 for ciliary import; GEF activity of Rab8 disassembles the complexes and releases free cargoes at the ciliary membrane. | Madugula and Lu (2016) |
| TNPO1 | KIF17 | CLS | TNPO1 binds the CLS of KIF17 targets it to the cilium; GTP-locked RAN mutant abolishes ciliary entry. | Dishinger et al. (2010) |
| Importin alpha/beta-1 dimer b | classical NLS | Importin alpha/beta-1 binds the NLS of KIF17 required for nuclear import. | Funabashi et al. (2017) | |
| TNPO1 | Gli2 transcriptional activator of Hh | PY-type NLS | TNPO1 regulates ciliary localisation of Gli2; TNPO1 is itself a transcriptional target of Hh, generating a feed forward loop for Gli2 activation in cilia. | Han et. al. (2017) |
| Importin alpha/beta-1 dimer b | classical NLS | Importin alpha/beta-1 binding to NLS is required for Gli2 nuclear import, not for ciliary import. | Torrado et al. (2016) | |
| Modulation / reversal of phase separation of aggregation-prone proteins | ||||
| TNPO1 | FUS | PY-type NLS | TNPO1 binds FUS and disperses aggregates fromed by intrnsically disordered domains. NLS mutations in FUS prevent TNPO1 binding and aggregate dispersal. | Dormann et al. (2010), Yoshizawa et al. (2018) |
| Importin alpha/beta-1 dimer | TDP-43 | NLS | Importin alpha/beta-1 binding to NLS of TDP-43 disrupts its dimerisation interface and prevents the formation of aggregates. | Guo et al. (2018), Doll et al. (2022) |
| TNPO1 | RNA-binding proteins (RBPs) hnRNPA1, hnRNPA2, FUS, TDP-43 | PY-NLS-type | TNPO1 engages th PY-NLSs in hnRNPA1 and hnRNPA2, reversing their fibrillisation. TNPO1 dissolves phase-separation of hydrogels formed by FUS and hnRNPA1. In vivo TNPO1 prevents the accumulation of PY-NLS-containing RBPs (TDP-43, FUS, hnRNPA1, hnRNPA2) in stress granules, restores RBP nuclear localisation, and rescues degeneration caused by disease-linked FUS and hnRNPA2. | Guo et al. (2018) |
| Importin beta-1 and importin alpha/beta-1 dimer | C9ORF72 | Arginine-containing dipeptide repeats (R-DPRs) may act as non canonical importin beta-1 binding sites | Importin beta-1 binds R-DPRs, which induce protein aggregation. This binding interferes with cargo loading onto importins, impairing nuclear import (including of TDP-43). R-DPRs promote phase separation and insolubility of TDP-43, which is suppressed by elevating importin concentrations. | Hayes et al. (2020), Hutten et al. (2020), Nanaura et al. (2021) |
| Importin alpha-7 | hnRNP R, hnRNP U | Bipartite NLS in hnRNP R and monopartite NLS in hnRNP U | Epilepsy-associated E344Q mutation in importin alpha-7 reduces its binding to NLSs, limiting importin alpha-7 binding to both hnRNP R and hnRNP U in iPSCs-derived neurons. Mutations in the hnRNP R bipartite NLS are associated with brain and cerebellar abnormalities. | Oostdyk et al. (2020) |
a
Only SAFs regulated by NIRs in late mitosis are listed. For NIR-regulated SAFs during mitosis proper see Forbes et al., 2015; Cavazza and Vernos, 2016
b
NIRs responsible for nuclear import can be genetically separated from those responsible for ciliary transport.