bims-nucpor Biomed News
on Nuclear pore complex and nucleoporins in stress, aging and disease
Issue of 2021–05–02
seven papers selected by
Sara Mingu, Johannes Gutenberg University
  1. O-GlcNAc modification of nuclear pore complexes accelerates bidirectional transport.
  2. Nucleocytoplasmic Transport: Regulatory Mechanisms and the Implications in Neurodegeneration.
  3. On the asymmetric partitioning of nucleocytoplasmic transport - recent insights and open questions.
  4. The Nuclear Transport Protein Importin-5: A Promising Target in Oncology and Virology.
  5. Quality control of mislocalized and orphan proteins.
  6. Current Approaches and Future Directions for the Treatment of mTORopathies.
  7. Intersection between Redox Homeostasis and Autophagy: Valuable Insights into Neurodegeneration.
  1. J Cell Biol. 2021 Jul 05. pii: e202010141. [Epub ahead of print]220(7):
    O-GlcNAc modification of nuclear pore complexes accelerates bidirectional transport.
    Tae Yeon Yoo, Timothy J Mitchison.
      Macromolecular transport across the nuclear envelope depends on facilitated diffusion through nuclear pore complexes (NPCs). The interior of NPCs contains a permeability barrier made of phenylalanine-glycine (FG) repeat domains that selectively facilitates the permeation of cargoes bound to nuclear transport receptors (NTRs). FG-repeat domains in NPCs are a major site of O-linked N-acetylglucosamine (O-GlcNAc) modification, but the functional role of this modification in nucleocytoplasmic transport is unclear. We developed high-throughput assays based on optogenetic probes to quantify the kinetics of nuclear import and export in living human cells. We found that increasing O-GlcNAc modification of the NPC accelerated NTR-facilitated transport of proteins in both directions, and decreasing modification slowed transport. Superresolution imaging revealed strong enrichment of O-GlcNAc at the FG-repeat barrier. O-GlcNAc modification also accelerated passive permeation of a small, inert protein through NPCs. We conclude that O-GlcNAc modification accelerates nucleocytoplasmic transport by enhancing the nonspecific permeability of the FG-repeat barrier, perhaps by steric inhibition of interactions between FG repeats.
    DOI:  https://doi.org/10.1083/jcb.202010141
  2. Int J Mol Sci. 2021 Apr 17. pii: 4165. [Epub ahead of print]22(8):
    Nucleocytoplasmic Transport: Regulatory Mechanisms and the Implications in Neurodegeneration.
    Baojin Ding, Masood Sepehrimanesh.
      Nucleocytoplasmic transport (NCT) across the nuclear envelope is precisely regulated in eukaryotic cells, and it plays critical roles in maintenance of cellular homeostasis. Accumulating evidence has demonstrated that dysregulations of NCT are implicated in aging and age-related neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), and Huntington disease (HD). This is an emerging research field. The molecular mechanisms underlying impaired NCT and the pathogenesis leading to neurodegeneration are not clear. In this review, we comprehensively described the components of NCT machinery, including nuclear envelope (NE), nuclear pore complex (NPC), importins and exportins, RanGTPase and its regulators, and the regulatory mechanisms of nuclear transport of both protein and transcript cargos. Additionally, we discussed the possible molecular mechanisms of impaired NCT underlying aging and neurodegenerative diseases, such as ALS/FTD, HD, and AD.
    Keywords:  Alzheimer’s disease; Huntington disease; Ran GTPase; amyotrophic lateral sclerosis; neurodegenerative diseases; nuclear pore complex; nucleocytoplasmic transport
    DOI:  https://doi.org/10.3390/ijms22084165
  3. J Cell Sci. 2021 Apr 01. pii: jcs240382. [Epub ahead of print]134(7):
    On the asymmetric partitioning of nucleocytoplasmic transport - recent insights and open questions.
    Joanna Kalita, Larisa E Kapinos, Roderick Y H Lim.
      Macromolecular cargoes are asymmetrically partitioned in the nucleus or cytoplasm by nucleocytoplasmic transport (NCT). At the center of this activity lies the nuclear pore complex (NPC), through which soluble factors circulate to orchestrate NCT. These include cargo-carrying importin and exportin receptors from the β-karyopherin (Kapβ) family and the small GTPase Ran, which switches between guanosine triphosphate (GTP)- and guanosine diphosphate (GDP)-bound forms to regulate cargo delivery and compartmentalization. Ongoing efforts have shed considerable light on how these soluble factors traverse the NPC permeability barrier to sustain NCT. However, this does not explain how importins and exportins are partitioned in the cytoplasm and nucleus, respectively, nor how a steep RanGTP-RanGDP gradient is maintained across the nuclear envelope. In this Review, we peel away the multiple layers of control that regulate NCT and juxtapose unresolved features against known aspects of NPC function. Finally, we discuss how NPCs might function synergistically with Kapβs, cargoes and Ran to establish the asymmetry of NCT.
    Keywords:  FG nucleoporin; Karyopherin; Nuclear pore complex; Nuclear transport receptor; Nucleocytoplasmic transport; Ran cycle
    DOI:  https://doi.org/10.1242/jcs.240382
  4. Chimia (Aarau). 2021 Apr 28. 75(4): 319-322
    The Nuclear Transport Protein Importin-5: A Promising Target in Oncology and Virology.
    Rémi Patouret.
      Cellular homeostasis importantly relies on the correct nucleoplasmic distribution of a large number of RNA molecules and proteins, which are shuttled by specialized transport receptors. The nuclear import receptor importin-5, also called IPO5, RanBP5 or karyopherin β3, mediates the translocation of proteins to the nucleus, and thus regulates critical signaling pathways and cellular functions. The normal function of IPO5 appears to be disrupted in cancer cells due to aberrant overexpression. IPO5 also demonstrated a pivotal role in viral replication. The constant increasing number of publications shows an interest within the scientific community as a therapeutic target due to its pivotal role in protein trafficking.
    DOI:  https://doi.org/10.2533/chimia.2021.319
  5. Exp Cell Res. 2021 Apr 28. pii: S0014-4827(21)00149-X. [Epub ahead of print] 112617
    Quality control of mislocalized and orphan proteins.
    Ka-Yiu Edwin Kong, João P L Coelho, Matthias J Feige, Anton Khmelinskii.
      A healthy and functional proteome is essential to cell physiology. However, this is constantly being challenged as most steps of protein metabolism are error-prone and changes in the physico-chemical environment can affect protein structure and function, thereby disrupting proteome homeostasis. Among a variety of potential mistakes, proteins can be targeted to incorrect compartments or subunits of protein complexes may fail to assemble properly with their partners, resulting in the formation of mislocalized and orphan proteins, respectively. Quality control systems are in place to handle these aberrant proteins, and to minimize their detrimental impact on cellular functions. Here, we discuss recent findings on quality control mechanisms handling mislocalized and orphan proteins. We highlight common principles involved in their recognition and summarize how accumulation of these aberrant molecules is associated with aging and disease.
    Keywords:  ageing; orphan proteins; protein mislocalization; protein quality control; proteostasis; selective protein degradation; ubiquitinproteasome system
    DOI:  https://doi.org/10.1016/j.yexcr.2021.112617
  6. Dev Neurosci. 2021 Apr 28. 1-16
    Current Approaches and Future Directions for the Treatment of mTORopathies.
    Vasiliki Karalis, Helen S Bateup.
      The mechanistic target of rapamycin (mTOR) is a kinase at the center of an evolutionarily conserved signaling pathway that orchestrates cell growth and metabolism. mTOR responds to an array of intra- and extracellular stimuli and in turn controls multiple cellular anabolic and catabolic processes. Aberrant mTOR activity is associated with numerous diseases, with particularly profound impact on the nervous system. mTOR is found in two protein complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2), which are governed by different upstream regulators and have distinct cellular actions. Mutations in genes encoding for mTOR regulators result in a collection of neurodevelopmental disorders known as mTORopathies. While these disorders can affect multiple organs, neuropsychiatric conditions such as epilepsy, intellectual disability, and autism spectrum disorder have a major impact on quality of life. The neuropsychiatric aspects of mTORopathies have been particularly challenging to treat in a clinical setting. Current therapeutic approaches center on rapamycin and its analogs, drugs that are administered systemically to inhibit mTOR activity. While these drugs show some clinical efficacy, adverse side effects, incomplete suppression of mTOR targets, and lack of specificity for mTORC1 or mTORC2 may limit their utility. An increased understanding of the neurobiology of mTOR and the underlying molecular, cellular, and circuit mechanisms of mTOR-related disorders will facilitate the development of improved therapeutics. Animal models of mTORopathies have helped unravel the consequences of mTOR pathway mutations in specific brain cell types and developmental stages, revealing an array of disease-related phenotypes. In this review, we discuss current progress and potential future directions for the therapeutic treatment of mTORopathies with a focus on findings from genetic mouse models.
    Keywords:  Epilepsy; Neurodevelopmental disorders; PTEN; Rapamycin; Raptor; Rictor; Tuberous sclerosis complex; mTORC1; mTORC2; mTORopathy
    DOI:  https://doi.org/10.1159/000515672
  7. Antioxidants (Basel). 2021 Apr 28. pii: 694. [Epub ahead of print]10(5):
    Intersection between Redox Homeostasis and Autophagy: Valuable Insights into Neurodegeneration.
    Hyungsun Park, Jongyoon Kim, Chihoon Shin, Seongju Lee.
      Autophagy, a main degradation pathway for maintaining cellular homeostasis, and redox homeostasis have recently been considered to play protective roles in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Increased levels of reactive oxygen species (ROS) in neurons can induce mitochondrial damage and protein aggregation, thereby resulting in neurodegeneration. Oxidative stress is one of the major activation signals for the induction of autophagy. Upon activation, autophagy can remove ROS, damaged mitochondria, and aggregated proteins from the cells. Thus, autophagy can be an effective strategy to maintain redox homeostasis in the brain. However, the interaction between redox homeostasis and autophagy is not clearly elucidated. In this review, we discuss recent studies on the relationship between redox homeostasis and autophagy associated with neurodegenerative diseases and propose that autophagy induction through pharmacological intervention or genetic activation might be a promising strategy to treat these disorders.
    Keywords:  ROS; autophagy; neurodegenerative diseases; redox homeostasis
    DOI:  https://doi.org/10.3390/antiox10050694
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