bims-nucpor Biomed News
on Nuclear pore complex and nucleoporins in stress, aging and disease
Issue of 2021‒09‒05
three papers selected by
Sara Mingu
Johannes Gutenberg University

  1. J Mol Biol. 2021 Aug 28. pii: S0022-2836(21)00453-8. [Epub ahead of print] 167220
      Nuclear-import receptors (NIRs) engage nuclear-localization signals (NLSs) of polypeptides in the cytoplasm and transport these cargo across the size-selective barrier of the nuclear-pore complex into the nucleoplasm. Beyond this canonical role in nuclear transport, NIRs operate in the cytoplasm to chaperone and disaggregate NLS-bearing clients. Indeed, NIRs can inhibit and reverse functional and deleterious phase transitions of their cargo, including several prominent neurodegenerative disease-linked RNA-binding proteins (RBPs) with prion-like domains (PrLDs), such as TDP-43, FUS, EWSR1, TAF15, hnRNPA1, and hnRNPA2. Importantly, elevated NIR expression can mitigate degenerative phenotypes connected to aberrant cytoplasmic aggregation of RBPs with PrLDs. Here, we review recent discoveries that NIRs can also antagonize aberrant interactions and toxicity of arginine-rich, dipeptide-repeat proteins that are associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) caused by G4C2 hexanucleotide repeat expansions in the first intron of C9ORF72. We also highlight recent findings that multiple NIR family members can prevent and reverse liquid-liquid phase separation of specific clients bearing RGG motifs in an NLS-independent manner. Finally, we discuss strategies to enhance NIR activity or expression, which could have therapeutic utility for several neurodegenerative disorders, including ALS, FTD, multisystem proteinopathy, limbic-predominant age-related TDP-43 encephalopathy, tauopathies, and related diseases.
  2. Mol Biol Cell. 2021 Sep 02. mbcE21040161
      Nucleocytoplasmic transport is a vital cellular process yet to be fully understood. Among several elements that are involved in the transport process, FG Nups are the major role players. We observed that specific sequence features (called like-charge regions, or lpLCRs), namely the extended sub-sequences that only possess positively charged amino acids, significantly affect the conformation of FG Nups inside the NPC. Here we investigate how the presence of lpLCRs affects the interactions between FG Nups and their interactions with cargo complex. We combined coarse-grained molecular dynamics simulations with time-resolved force distribution analysis to disordered proteins to explore the behavior of the system. Our results suggest that the number of charged residues in the lpLCR domain directly governs the average distance between Phe residues and the intensity of interaction between them. As a result, the number of charged residues within and lpLCR determines the balance between the hydrophobic interaction and electrostatic repulsion and governs how disordered the hydrophobic network formed by FG Nups. Moreover, changing the number of charged residues in an lpLCR domain can interfere with ultrafast and transient interactions between FG Nups and cargo complex. [Media: see text] [Media: see text] [Media: see text].
  3. Curr Opin Virol. 2021 Aug 28. pii: S1879-6257(21)00092-4. [Epub ahead of print]50 147-158
      Starting a herpesviral infection is a steeplechase across membranes, cytosol, and nuclear envelopes and against antiviral defence mechanisms. Here, we highlight recent insights on capsid stabilization at the portals during assembly, early capsid-host interactions ensuring nuclear targeting of incoming capsids, and genome uncoating. After fusion with a host membrane, incoming capsids recruit microtubule motors for traveling to the centrosome, and by unknown mechanisms get forward towards the nucleus. The interaction of capsid-associated tegument proteins with nucleoporins orients the capsid portal towards the nuclear pore, and presumably after removal of the portal caps the genomes that have been packaged under pressure can be injected into the nucleoplasm for transcription and replication. Some cell types disarm the incoming capsids or silence the incoming genomes to reduce the likelihood of infection.