bims-nucpor Biomed News
on Nuclear pore complex and nucleoporins in stress, aging and disease
Issue of 2023‒08‒27
seven papers selected by
Sara Mingu, Johannes Gutenberg University
  1. The nuclear pore complex as a platform for epigenetic regulation.
  2. Coordinating nucleoporin condensation and nuclear pore complex assembly.
  3. Interdependent changes of nuclear lamins, nuclear pore complexes, and ploidy regulate cellular regeneration and stress response in the heart.
  4. Dynamics of nuclear export of pre-ribosomal subunits revealed by high-speed single-molecule microscopy in live cells.
  5. Virus Infection and mRNA Nuclear Export.
  6. Nucleocytoplasmic transport at the crossroads of proteostasis, neurodegeneration and neuroprotection.
  7. Therapeutic targeting of nuclear export and import receptors in cancer and their potential in combination chemotherapy.
  1. J Cell Biol. 2023 09 04. pii: e202307078. [Epub ahead of print]222(9):
    The nuclear pore complex as a platform for epigenetic regulation.
    Jason H Brickner.
      The nuclear pore complex (NPC) both mediates exchange of proteins and RNA between the nucleus and the cytoplasm and physically interacts with chromatin to regulate transcription. In this issue of JCB, Kumar et al. (2023. J. Cell Biol.https://doi.org/10.1083/jcb.202207060) provide new insight into the molecular basis for NPC-mediated epigenetic silencing through loading of the replication processivity factor PCNA.
    DOI:  https://doi.org/10.1083/jcb.202307078
  2. FEBS Lett. 2023 Aug 24.
    Coordinating nucleoporin condensation and nuclear pore complex assembly.
    E F Elsiena Kuiper, Sarah M Prophet, Christian Schlieker.
      The nuclear pore complex (NPC) is among the most elaborate protein complexes in eukaryotes. While ribosomes and proteasomes are known to require dedicated assembly machinery, our understanding of NPC assembly is at a relatively early stage. Defects in NPC assembly or homeostasis are tied to movement disorders, including dystonia and amyotrophic lateral sclerosis (ALS), as well as aging, requiring a better understanding of these processes to enable therapeutic intervention. Here, we discuss recent progress in the understanding of NPC assembly and highlight how related defects in human disorders can shed light on NPC biogenesis. We propose that the condensation of phenylalanine-glycine repeat nucleoporins needs to be carefully controlled during NPC assembly to prevent aberrant condensation, aggregation, or amyloid formation.
    Keywords:  condensation; fusogen; membrane fusion; molecular chaperones; nuclear envelope; nuclear pore complex; phase separation
    DOI:  https://doi.org/10.1002/1873-3468.14725
  3. Nucleus. 2023 Dec;14(1): 2246310
    Interdependent changes of nuclear lamins, nuclear pore complexes, and ploidy regulate cellular regeneration and stress response in the heart.
    Yao Li, Alberto Bertozzi, Mellissa Rw Mann, Bernhard Kühn.
      In adult mammals, many heart muscle cells (cardiomyocytes) are polyploid, do not proliferate (post-mitotic), and, consequently, cannot contribute to heart regeneration. In contrast, fetal and neonatal heart muscle cells are diploid, proliferate, and contribute to heart regeneration. We have identified interdependent changes of the nuclear lamina, nuclear pore complexes, and DNA-content (ploidy) in heart muscle cell maturation. These results offer new perspectives on how cells alter their nuclear transport and, with that, their gene regulation in response to extracellular signals. We present how changes of the nuclear lamina alter nuclear pore complexes in heart muscle cells. The consequences of these changes for cellular regeneration and stress response in the heart are discussed.
    Keywords:  Cardiac hypertrophy; cardiac remodeling; cardiomyocyte; heart regeneration; nuclear lamina; nuclear pore; nuclear transport
    DOI:  https://doi.org/10.1080/19491034.2023.2246310
  4. iScience. 2023 Aug 18. 26(8): 107445
    Dynamics of nuclear export of pre-ribosomal subunits revealed by high-speed single-molecule microscopy in live cells.
    Samuel L Junod, Mark Tingey, Joseph M Kelich, Alexander Goryaynov, Karl Herbine, Weidong Yang.
      We present a study on the nuclear export efficiency and time of pre-ribosomal subunits in live mammalian cells, using high-speed single-molecule tracking and single-molecule fluorescence resonance energy transfer techniques. Our findings reveal that pre-ribosomal particles exhibit significantly higher nuclear export efficiency compared to other large cargos like mRNAs, with around two-thirds of interactions between the pre-60S or pre-40S and the nuclear pore complexes (NPCs) resulting in successful export to the cytoplasm. We also demonstrate that nuclear transport receptor (NTR) chromosomal maintenance 1 (CRM1) plays a crucial role in nuclear export efficiency, with pre-60S and pre-40S particle export efficiency decreasing by 11-17-fold when CRM1 is inhibited. Our results suggest that multiple copies of CRM1 work cooperatively to chaperone pre-ribosomal subunits through the NPC, thus increasing export efficiency and decreasing export time. Significantly, this cooperative NTR mechanism extends beyond pre-ribosomal subunits, as evidenced by the enhanced nucleocytoplasmic transport of proteins.
    Keywords:  Biological sciences; Cell biology; Functional aspects of cell biology; Natural sciences; Organizational aspects of cell biology
    DOI:  https://doi.org/10.1016/j.isci.2023.107445
  5. Int J Mol Sci. 2023 Aug 09. pii: 12593. [Epub ahead of print]24(16):
    Virus Infection and mRNA Nuclear Export.
    Jiayin Guo, Yaru Zhu, Xiaoya Ma, Guijun Shang, Bo Liu, Ke Zhang.
      Gene expression in eukaryotes begins with transcription in the nucleus, followed by the synthesis of messenger RNA (mRNA), which is then exported to the cytoplasm for its translation into proteins. Along with transcription and translation, mRNA export through the nuclear pore complex (NPC) is an essential regulatory step in eukaryotic gene expression. Multiple factors regulate mRNA export and hence gene expression. Interestingly, proteins from certain types of viruses interact with these factors in infected cells, and such an interaction interferes with the mRNA export of the host cell in favor of viral RNA export. Thus, these viruses hijack the host mRNA nuclear export mechanism, leading to a reduction in host gene expression and the downregulation of immune/antiviral responses. On the other hand, the viral mRNAs successfully evade the host surveillance system and are efficiently exported from the nucleus to the cytoplasm for translation, which enables the continuation of the virus life cycle. Here, we present this review to summarize the mechanisms by which viruses suppress host mRNA nuclear export during infection, as well as the key strategies that viruses use to facilitate their mRNA nuclear export. These studies have revealed new potential antivirals that may be used to inhibit viral mRNA transport and enhance host mRNA nuclear export, thereby promoting host gene expression and immune responses.
    Keywords:  CRM1; NPC; NXF1; Nup98; Rae1; host mRNA; mRNA export; viral mRNA; virus
    DOI:  https://doi.org/10.3390/ijms241612593
  6. FEBS Lett. 2023 Aug 19.
    Nucleocytoplasmic transport at the crossroads of proteostasis, neurodegeneration and neuroprotection.
    Paulo A Ferreira.
      Nucleocytoplasmic transport comprises the multistep assembly, transport, and disassembly of protein and RNA cargoes entering and exiting nuclear pores. Accruing evidence supports that impairments to nucleocytoplasmic transport are a hallmark of neurodegenerative diseases. These impairments cause dysregulations in nucleocytoplasmic partitioning and proteostasis of nuclear transport receptors and client substrates that promote intracellular deposits - another hallmark of neurodegeneration. Disturbances in liquid-liquid phase separation (LLPS) between dense and dilute phases of biomolecules implicated in nucleocytoplasmic transport promote micrometer-scale coacervates, leading to proteinaceous aggregates. This Review provides historical and emerging principles of LLPS at the interface of nucleocytoplasmic transport, proteostasis, aging and noxious insults, whose dysregulations promote intracellular aggregates. E3 SUMO-protein ligase Ranbp2 constitutes the cytoplasmic filaments of nuclear pores, where it acts as a molecular hub for rate-limiting steps of nucleocytoplasmic transport. A vignette is provided on the roles of Ranbp2 in nucleocytoplasmic transport and at the intersection of proteostasis in the survival of photoreceptor and motor neurons under homeostatic and pathophysiological environments. Current unmet clinical needs are highlighted, including therapeutics aiming to manipulate aggregation-dissolution models of purported neurotoxicity in neurodegeneration.
    Keywords:  Ran-binding protein 2; chaperone; cyclophilin; liquid-liquid phase separation; motoneuron; neurodegeneration; neuroprotection; nucleocytoplasmic transport; photoreceptor neuron; protein aggregation
    DOI:  https://doi.org/10.1002/1873-3468.14722
  7. IUBMB Life. 2023 Aug 25.
    Therapeutic targeting of nuclear export and import receptors in cancer and their potential in combination chemotherapy.
    Stella Newell, Pauline J van der Watt, Virna D Leaner.
      Systemic modalities are crucial in the management of disseminated malignancies and liquid tumours. However, patient responses and tolerability to treatment are generally poor and those that enter remission often return with refractory disease. Combination therapies provide a methodology to overcome chemoresistance mechanisms and address dose-limiting toxicities. A deeper understanding of tumorigenic processes at the molecular level has brought a targeted therapy approach to the forefront of cancer research, and novel cancer biomarkers are being identified at a rapid rate, with some showing potential therapeutic benefits. The Karyopherin superfamily of proteins is soluble receptors that mediate nucleocytoplasmic shuttling of proteins and RNAs, and recently, nuclear transport receptors have been recognized as novel anticancer targets. Inhibitors against nuclear export have been approved for clinical use against certain cancer types, whereas inhibitors against nuclear import are in preclinical stages of investigation. Mechanistically, targeting nucleocytoplasmic shuttling has shown to abrogate oncogenic signalling and restore tumour suppressor functions through nuclear sequestration of relevant proteins and mRNAs. Hence, nuclear transport inhibitors display broad spectrum anticancer activity and harbour potential to engage in synergistic interactions with a wide array of cytotoxic agents and other targeted agents. This review is focussed on the most researched nuclear transport receptors in the context of cancer, XPO1 and KPNB1, and highlights how inhibitors targeting these receptors can enhance the therapeutic efficacy of standard of care therapies and novel targeted agents in a combination therapy approach. Furthermore, an updated review on the therapeutic targeting of lesser characterized karyopherin proteins is provided and resistance to clinically approved nuclear export inhibitors is discussed.
    Keywords:  KPNB1; XPO1; cancer; combination therapy; nuclear transport proteins; targeted therapy
    DOI:  https://doi.org/10.1002/iub.2773
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