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

Abstract

Extensive structural and functional studies have been carried out in the field of nucleocytoplasmic transport. Nuclear transport factors, such as Importin-a/-b, 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.

Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinases (DYRKs) and cdc2-Like Kinases (CLKs) in Human Disease, an Overview

“…Autophosphorylation on the tyrosine residue is preceded by hydroxylation of a proline residue by the PHD1 prolyl hydroxylase, an absolute requirement for catalytic activation of the kinase [ 19 ]. The N-terminal domain of all DYRKs except DYRK3 contains a nuclear localization signal domain (NLS) [ 20 ]. DYRK2, DYRK3, and DYRK4 contain a conserved N-terminal autophosphorylation accessory (NAPA) domain essential for autophosphorylation of the activation loop tyrosine [ 21 ].…”

A new monoclonal antibody enables BAR analysis of subcellular importin β1 interactomes

“…Gene ontology analyses from datasets of (1) Reference #17 (HEK293T), (2) References #18,#19 (HeLa) (3) HEK 293T BAR (4) DRG neuron BAR. (A) Canonical pathway comparison using Ingenuity pathway analysis sorted by score value and a 1% p value cut-off.…”

Dominant KPNA3 Mutations Cause Infantile‐Onset Hereditary Spastic Paraplegia

“…Along the same lines, all HSP-associated karyopherin-α3 variants are found to exhibit diminished binding to RCC1, a crucial player in safeguarding Ran-GTP/-GDP gradients and thus the directionality of nucleocytoplasmic trafficking. 11 As a consequence, both loss of function owing to nuclear depletion and gain-of-function mechanisms resulting from enhanced cytoplasmic levels of karyophilic proteins might contribute to HSP pathogenesis. Whether the latter involves an increased propensity of nuclear proteins to accumulate in pathogenic cytoplasmic inclusions similar to those observed in degenerating neurons of other neurodegenerative disorders, such as ALS, FTD, and multisystem proteinopathy, awaits further analysis.…”

“…9,10 Nucleocytoplasmic trafficking requires various highly conserved components, including nuclear transport receptors (NTRs; also referred to as karyopherins/importins), a nuclear localization signal (NLS) within the protein cargo, and constituents of the Ran GTPase cycle. 11,12 Importantly, different ALS-associated pathogenic missense variants affecting the NLS of FUS alter both its NTR binding and subcellular localization, further implicating nucleocytoplasmic trafficking in the pathogenesis of neurodegeneration. 10 In addition to their canonical role in nucleocytoplasmic protein trafficking, NTRs also appear to control the formation and function of different supramolecular assemblies by fine-tuning the phase-separating properties of RBPs, a function that again has implications for various neurodegenerative diseases, including ALS.…”