bims-nucpor Biomed News
on Nuclear pore complex and nucleoporins in stress, aging and disease
Issue of 2023–09–10
six papers selected by
Sara Mingu, Johannes Gutenberg University
  1. Caspase-mediated nuclear pore complex trimming in cell differentiation and endoplasmic reticulum stress.
  2. The role of nuclear pores and importins for herpes simplex virus infection.
  3. Deviating from the norm: Nuclear organisation in trypanosomes.
  4. Structural convergence endows nuclear transport receptor Kap114p with a transcriptional repressor function toward TATA-binding protein.
  5. Brief excitotoxic insults cause a calpain-mediated increase in nuclear membrane permeability in neonatal neurons.
  6. A feedback loop between heterochromatin and the nucleopore complex controls germ-cell-to-oocyte transition during Drosophila oogenesis.
  1. Elife. 2023 09 04. pii: RP89066. [Epub ahead of print]12
    Caspase-mediated nuclear pore complex trimming in cell differentiation and endoplasmic reticulum stress.
    Ukrae H Cho, Martin W Hetzer.
      During apoptosis, caspases degrade 8 out of ~30 nucleoporins to irreversibly demolish the nuclear pore complex. However, for poorly understood reasons, caspases are also activated during cell differentiation. Here, we show that sublethal activation of caspases during myogenesis results in the transient proteolysis of four peripheral Nups and one transmembrane Nup. 'Trimmed' NPCs become nuclear export-defective, and we identified in an unbiased manner several classes of cytoplasmic, plasma membrane, and mitochondrial proteins that rapidly accumulate in the nucleus. NPC trimming by non-apoptotic caspases was also observed in neurogenesis and endoplasmic reticulum stress. Our results suggest that caspases can reversibly modulate nuclear transport activity, which allows them to function as agents of cell differentiation and adaptation at sublethal levels.
    Keywords:  caspase; cell biology; cell differentiation; developmental biology; mouse; nuclear pore complex
    DOI:  https://doi.org/10.7554/eLife.89066
  2. Curr Opin Virol. 2023 Sep 04. pii: S1879-6257(23)00061-5. [Epub ahead of print]62 101361
    The role of nuclear pores and importins for herpes simplex virus infection.
    Katinka Döhner, Manutea C Serrero, Beate Sodeik.
      Microtubule transport and nuclear import are functionally connected, and the nuclear pore complex (NPC) can interact with microtubule motors. For several alphaherpesvirus proteins, nuclear localization signals (NLSs) and their interactions with specific importin-α proteins have been characterized. Here, we review recent insights on the roles of microtubule motors, capsid-associated NLSs, and importin-α proteins for capsid transport, capsid docking to NPCs, and genome release into the nucleoplasm, as well as the role of importins for nuclear viral transcription, replication, capsid assembly, genome packaging, and nuclear capsid egress. Moreover, importin-α proteins exert antiviral effects by promoting the nuclear import of transcription factors inducing the expression of interferons (IFN), cytokines, and IFN-stimulated genes, and the IFN-inducible MxB restricts capsid docking to NPCs.
    DOI:  https://doi.org/10.1016/j.coviro.2023.101361
  3. Curr Opin Cell Biol. 2023 Sep 02. pii: S0955-0674(23)00083-2. [Epub ahead of print]85 102234
    Deviating from the norm: Nuclear organisation in trypanosomes.
    Mark C Field.
      At first glance the nucleus is a highly conserved organelle. Overall nuclear morphology, the octagonal nuclear pore complex, the presence of peripheral heterochromatin and the nuclear envelope appear near constant features right down to the ultrastructural level. New work is revealing significant compositional divergence within these nuclear structures and their associated functions, likely reflecting adaptations and distinct mechanisms between eukaryotic lineages and especially the trypanosomatids. While many examples of mechanistic divergence currently lack obvious functional interpretations, these studies underscore the malleability of nuclear architecture. I will discuss some recent findings highlighting these facets within trypanosomes, together with the underlying evolutionary framework and make a call for the exploration of nuclear function in non-canonical experimental organisms.
    Keywords:  Eukaryogenesis; Lamina; Lamins; Molecular evolution; Nuclear architecture; Nuclear envelope; Nuclear pore complex; Trypanosomes
    DOI:  https://doi.org/10.1016/j.ceb.2023.102234
  4. Nat Commun. 2023 Sep 08. 14(1): 5518
    Structural convergence endows nuclear transport receptor Kap114p with a transcriptional repressor function toward TATA-binding protein.
    Chung-Chi Liao, Yi-Sen Wang, Wen-Chieh Pi, Chun-Hsiung Wang, Yi-Min Wu, Wei-Yi Chen, Kuo-Chiang Hsia.
      The transcription factor TATA-box binding protein (TBP) modulates gene expression in nuclei. This process requires the involvement of nuclear transport receptors, collectively termed karyopherin-β (Kap-β) in yeast, and various regulatory factors. In previous studies we showed that Kap114p, a Kap-β that mediates nuclear import of yeast TBP (yTBP), modulates yTBP-dependent transcription. However, how Kap114p associates with yTBP to exert its multifaceted functions has remained elusive. Here, we employ single-particle cryo-electron microscopy to determine the structure of Kap114p in complex with the core domain of yTBP (yTBPC). Remarkably, Kap114p wraps around the yTBPC N-terminal lobe, revealing a structure resembling transcriptional regulators in complex with TBP, suggesting convergent evolution of the two protein groups for a common function. We further demonstrate that Kap114p sequesters yTBP away from promoters, preventing a collapse of yTBP dynamics required for yeast responses to environmental stress. Hence, we demonstrate that nuclear transport receptors represent critical elements of the transcriptional regulatory network.
    DOI:  https://doi.org/10.1038/s41467-023-41206-9
  5. bioRxiv. 2023 Aug 23. pii: 2023.08.22.554167. [Epub ahead of print]
    Brief excitotoxic insults cause a calpain-mediated increase in nuclear membrane permeability in neonatal neurons.
    P Suryavanshi, R Langton, K Fairhead, J Glykys.
      Neuronal edema after excitotoxic brain insults results in neuronal injury and death. Osmotic and surgical interventions designed to mitigate edema yield poor clinical outcomes, highlighting the need to explore other mechanisms. Concurrent with neuronal swelling, excessive Ca 2+ loading can be deleterious but remains poorly investigated, especially during the neonatal period. We used in and ex vivo multiphoton Ca 2+ imaging to evaluate the relationship between cytotoxic edema and Ca 2+ load in neonatal GCaMP6-expressing neurons after different and brief excitotoxic insults. We report acute translocation of cytosolic GCaMP6s into the nucleus of neonatal neurons after various short excitotoxic insults quantified as the ratio of nuclear: cytosolic intensity (N/C ratio). The increase in the N/C ratio occurred independently of neuronal swelling. Transmission electron microscopy revealed that elevated N/C ratios correlated with increased nuclear pore size in neurons. Inhibiting calpains in and ex vivo prevented increased N/C ratios and decreased neuronal swelling. Our results demonstrate that brief excitotoxic injury can enlarge nuclear pores and dysregulate nuclear transport in neurons through a calpain-mediated mechanism during early brain development. Additionally, N/C ratio measurements can be used to detect acute neuronal injury in real-time.
    Graphical abstract:
    DOI:  https://doi.org/10.1101/2023.08.22.554167
  6. Dev Cell. 2023 Aug 28. pii: S1534-5807(23)00412-4. [Epub ahead of print]
    A feedback loop between heterochromatin and the nucleopore complex controls germ-cell-to-oocyte transition during Drosophila oogenesis.
    Kahini Sarkar, Noor M Kotb, Alex Lemus, Elliot T Martin, Alicia McCarthy, Justin Camacho, Ayman Iqbal, Alex M Valm, Morgan A Sammons, Prashanth Rangan.
      Germ cells differentiate into oocytes that launch the next generation upon fertilization. How the highly specialized oocyte acquires this distinct cell fate is poorly understood. During Drosophila oogenesis, H3K9me3 histone methyltransferase SETDB1 translocates from the cytoplasm to the nucleus of germ cells concurrently with oocyte specification. Here, we discovered that nuclear SETDB1 is required for silencing a cohort of differentiation-promoting genes by mediating their heterochromatinization. Intriguingly, SETDB1 is also required for upregulating 18 of the ∼30 nucleoporins (Nups) that compose the nucleopore complex (NPC), promoting NPC formation. NPCs anchor SETDB1-dependent heterochromatin at the nuclear periphery to maintain H3K9me3 and gene silencing in the egg chambers. Aberrant gene expression due to the loss of SETDB1 or Nups results in the loss of oocyte identity, cell death, and sterility. Thus, a feedback loop between heterochromatin and NPCs promotes transcriptional reprogramming at the onset of oocyte specification, which is critical for establishing oocyte identity.
    Keywords:  NPC; SETDB1; differentiation; germ cells; germ line; heterochromatin; nucleopore complex; oocyte
    DOI:  https://doi.org/10.1016/j.devcel.2023.08.014
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