bims-nucpor Biomed News
on Nuclear pore complex and nucleoporins in stress, aging and disease
Issue of 2023–09–24
six papers selected by
Sara Mingu, Johannes Gutenberg University
  1. Changing the guard - nuclear pore complex quality control.
  2. Fellowship of two rings: Unprecedented insights into the structure of the yeast nuclear pore complex.
  3. Unraveling the impact of disrupted nucleocytoplasmic transport systems in C9orf72-associated ALS.
  4. Implications of a multiscale structure of the yeast nuclear pore complex.
  5. A R-loop sensing pathway mediates the relocation of transcribed genes to nuclear pore complexes.
  6. Evolutionarily conserved protein motifs drive interactions between the plant nucleoskeleton and nuclear pores.
  1. FEBS Lett. 2023 Sep 16.
    Changing the guard - nuclear pore complex quality control.
    Annemiek C Veldsink, Paola Gallardo, C Patrick Lusk, Liesbeth M Veenhoff.
      The integrity of the nuclear envelope (NE) depends on the function of nuclear pore complexes (NPCs), transport channels that control macromolecular traffic between the nucleus and cytosol. The central importance of NPCs suggests the existence of quality control (QC) mechanisms that oversee their assembly and function. In this perspective, we emphasize the challenges associated with NPC assembly and the need for QC mechanisms that operate at various stages of an NPC's life. This includes cytosolic pre-assembly QC that helps enforce key nucleoporin-nucleoporin interactions and their ultimate stoichiometry in the NPC in addition to mechanisms that monitor aberrant fusion of the inner and outer nuclear membranes. Furthermore, we discuss if and how these QC mechanisms may operate to sense faulty mature NPCs to facilitate their repair or removal. The so far uncovered mechanisms for NPC QC provide fertile ground for future research that not only benefits a better understanding of the vital role that NPCs play in cellular physiology but also how loss of NPC function and/or these QC mechanisms might be an input to ageing and disease.
    Keywords:  ESCRT; Nuclear pore complex; ageing; autophagy; membrane fusion; nuclear envelope; nuclear pore complex assembly; nuclear transport; proteostasis; quality control
    DOI:  https://doi.org/10.1002/1873-3468.14739
  2. Mol Cell. 2023 Sep 21. pii: S1097-2765(23)00691-3. [Epub ahead of print]83(18): 3232-3233
    Fellowship of two rings: Unprecedented insights into the structure of the yeast nuclear pore complex.
    Anita H Corbett, Milo B Fasken.
      Akey et al.1 use complementary experimental approaches and AI-based structure prediction to reveal new details of the structure of the yeast nuclear pore complex, providing key insights into evolution, assembly, and nucleocytoplasmic transport mechanisms.
    DOI:  https://doi.org/10.1016/j.molcel.2023.08.028
  3. Front Cell Neurosci. 2023 ;17 1247297
    Unraveling the impact of disrupted nucleocytoplasmic transport systems in C9orf72-associated ALS.
    Philip McGoldrick, Janice Robertson.
      Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two adult-onset neurodegenerative diseases that are part of a common disease spectrum due to clinical, genetic, and pathological overlap. A prominent genetic factor contributing to both diseases is a hexanucleotide repeat expansion in a non-coding region of the C9orf72 gene. This mutation in C9orf72 leads to nuclear depletion and cytoplasmic aggregation of Tar DNA-RNA binding protein 43 (TDP-43). TDP-43 pathology is characteristic of the majority of ALS cases, irrespective of disease causation, and is present in ~50% of FTD cases. Defects in nucleocytoplasmic transport involving the nuclear pore complex, the Ran-GTPase cycle, and nuclear transport factors have been linked with the mislocalization of TDP-43. Here, we will explore and discuss the implications of these system abnormalities of nucleocytoplasmic transport in C9orf72-ALS/FTD, as well as in other forms of familial and sporadic ALS.
    Keywords:  C9orf72; Ran-GTP; amyotrophic lateral sclerosis (ALS); frontotemporal dementia (FTD); nuclear pore complex (NPC); nucleocytoplasmic transport
    DOI:  https://doi.org/10.3389/fncel.2023.1247297
  4. Mol Cell. 2023 Sep 21. pii: S1097-2765(23)00661-5. [Epub ahead of print]83(18): 3283-3302.e5
    Implications of a multiscale structure of the yeast nuclear pore complex.
    Christopher W Akey, Ignacia Echeverria, Christna Ouch, Ilona Nudelman, Yi Shi, Junjie Wang, Brian T Chait, Andrej Sali, Javier Fernandez-Martinez, Michael P Rout.
      Nuclear pore complexes (NPCs) direct the nucleocytoplasmic transport of macromolecules. Here, we provide a composite multiscale structure of the yeast NPC, based on improved 3D density maps from cryogenic electron microscopy and AlphaFold2 models. Key features of the inner and outer rings were integrated into a comprehensive model. We resolved flexible connectors that tie together the core scaffold, along with equatorial transmembrane complexes and a lumenal ring that anchor this channel within the pore membrane. The organization of the nuclear double outer ring reveals an architecture that may be shared with ancestral NPCs. Additional connections between the core scaffold and the central transporter suggest that under certain conditions, a degree of local organization is present at the periphery of the transport machinery. These connectors may couple conformational changes in the scaffold to the central transporter to modulate transport. Collectively, this analysis provides insights into assembly, transport, and NPC evolution.
    Keywords:  AlphaFold2 modeling; FG repeats; computed structure models; cryo-EM; cryogenic electron microscopy; nuclear pore complex; nucleocytoplasmic transport; single-particle analysis
    DOI:  https://doi.org/10.1016/j.molcel.2023.08.025
  5. Nat Commun. 2023 09 20. 14(1): 5606
    A R-loop sensing pathway mediates the relocation of transcribed genes to nuclear pore complexes.
    Arianna Penzo, Marion Dubarry, Clémentine Brocas, Myriam Zheng, Raphaël M Mangione, Mathieu Rougemaille, Coralie Goncalves, Ophélie Lautier, Domenico Libri, Marie-Noëlle Simon, Vincent Géli, Karine Dubrana, Benoit Palancade.
      Nuclear pore complexes (NPCs) have increasingly recognized interactions with the genome, as exemplified in yeast, where they bind transcribed or damaged chromatin. By combining genome-wide approaches with live imaging of model loci, we uncover a correlation between NPC association and the accumulation of R-loops, which are genotoxic structures formed through hybridization of nascent RNAs with their DNA templates. Manipulating hybrid formation demonstrates that R-loop accumulation per se, rather than transcription or R-loop-dependent damages, is the primary trigger for relocation to NPCs. Mechanistically, R-loop-dependent repositioning involves their recognition by the ssDNA-binding protein RPA, and SUMO-dependent interactions with NPC-associated factors. Preventing R-loop-dependent relocation leads to lethality in hybrid-accumulating conditions, while NPC tethering of a model hybrid-prone locus attenuates R-loop-dependent genetic instability. Remarkably, this relocation pathway involves molecular factors similar to those required for the association of stalled replication forks with NPCs, supporting the existence of convergent mechanisms for sensing transcriptional and genotoxic stresses.
    DOI:  https://doi.org/10.1038/s41467-023-41345-z
  6. Plant Cell. 2023 Sep 21. pii: koad236. [Epub ahead of print]
    Evolutionarily conserved protein motifs drive interactions between the plant nucleoskeleton and nuclear pores.
    Sarah Mermet, Maxime Voisin, Joris Mordier, Tristan Dubos, Sylvie Tutois, Pierre Tuffery, Célia Baroux, Kentaro Tamura, Aline V Probst, Emmanuel Vanrobays, Christophe Tatout.
      The nucleoskeleton forms a filamentous meshwork under the nuclear envelope and contributes to the regulation of nuclear shape and gene expression. To understand how the Arabidopsis (Arabidopsis thaliana) nucleoskeleton physically connects to the nuclear periphery in plants, we investigated the Arabidopsis nucleoskeleton protein KAKU4 and sought for functional regions responsible for its localisation at the nuclear periphery. We identified three conserved peptide motifs within the N-terminal region of KAKU4 that are required for intermolecular interactions of KAKU4 with itself, interaction with the nucleoskeleton protein CROWDED NUCLEI (CRWN), localisation at the nuclear periphery and nuclear elongation in differentiated tissues. Unexpectedly, we find these motifs to be present also in NUP82 and NUP136, two plant specific nucleoporins from the nuclear pore basket. We further show that NUP82, NUP136 and KAKU4 have a common evolutionary history predating non-vascular land plants with KAKU4 mainly localising outside the nuclear pore suggesting its divergence from an ancient nucleoporin into a new nucleoskeleton component. Finally, we demonstrate that both NUP82 and NUP136, through their shared N-terminal motifs, interact with CRWN and KAKU4 proteins revealing the existence of a physical continuum between the nuclear pore and the nucleoskeleton in plants.
    DOI:  https://doi.org/10.1093/plcell/koad236
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