bims-nucpor Biomed News
on Nuclear pore complex and nucleoporins in stress, aging and disease
Issue of 2024–01–07
seven papers selected by
Sara Mingu, Johannes Gutenberg University
  1. Arabidopsis nucleoporin NUP96 mediates plant salt tolerance by modulating the transcription of salt-responsive genes.
  2. The Role of Nucleoporins in Cardiac Tissue Development and Disease.
  3. Nuclear pore pathology underlying multisystem proteinopathy type 3-related inclusion body myopathy.
  4. Highly variable molecular signatures of TDP-43 loss of function are associated with nuclear pore complex injury in a population study of sporadic ALS patient iPSNs.
  5. Nuclear pore protein POM121 regulates subcellular localization and transcriptional activity of PPARγ.
  6. Structural determinants of phosphorylation-dependent nuclear transport of HCMV DNA polymerase processivity factor UL44.
  7. Fluvoxamine Exerts Sigma-1R to Rescue Autophagy via Pom121-Mediated Nucleocytoplasmic Transport of TFEB.
  1. Planta. 2023 Dec 31. 259(2): 34
    Arabidopsis nucleoporin NUP96 mediates plant salt tolerance by modulating the transcription of salt-responsive genes.
    Xiaomin Yang, Chengcheng Ji, Xinxin Liu, Zhaoxin Wei, Qiuying Pang, Aiqin Zhang.
       MAIN CONCLUSION: Physiological and molecular tests show that NUP96 plays an important role in the plant response to salt stress, resulting from the reprogramming of transcriptomic profiles, which are likely to be mediated by the influence on the nuclear/cytosol shuttling of the key regulators of salt tolerance. As a key component of the nuclear pore complex (NPC), nucleoporin 96 (NUP96) is critical for modulating plant development and interactions with environmental factors, but whether NUP96 is involved in the salt response is still unknown. Here, we analyzed the role of Arabidopsis NUP96 under salt stress. The loss-of-function mutant nup96 exhibited salt sensitivity in terms of rosette growth and root elongation, and showed attenuated capacity in maintaining ion and ROS homeostasis, which could be compensated for by the overexpression of NUP96. RNA sequencing revealed that many salt-responsive genes were misregulated after NUP96 mutation, and especially NUP96 is required for the expression of a large portion of salt-induced genes. This is likely correlated with the activity in facilitating nuclear/cytosol transport of the underlying regulators in salt tolerance such as the transcription factor ATAP2, targeted by eight downregulated genes in nup96 under salt stress. Our results illustrate that NUP96 plays an important role in the salt response, probably by regulating the nucleocytoplasmic shuttling of key mRNAs or proteins associated with plant salt responsiveness.
    Keywords:  ATAP2; Nuclear pore complex; Nucleocytoplasmic transport; Nucleoporin 96 (NUP96); Salt stress
    DOI:  https://doi.org/10.1007/s00425-023-04312-y
  2. Front Biosci (Landmark Ed). 2023 Dec 27. 28(12): 350
    The Role of Nucleoporins in Cardiac Tissue Development and Disease.
    Xiaocong Chen, Rui Shi, Yu Luo, Liang Xu.
      Nuclear pore complexes (NPCs) are intricate intracellular structures composed of approximately 30 nuclear pore proteins (NUPs) that regulate the transport of materials between the nucleus and cytoplasm in eukaryotic cells. The heart is a crucial organ for sustaining the vital functions of the body, pumping blood rich in nutrients and energy to all organs and tissues. Recent studies have shown that NPCs play pivotal roles not only in normal cardiac physiological processes such as myocardial cell proliferation and differentiation but also in various pathological processes such as ischemic and hypoxic myocardial injury. Due to their mass and complicated nature, the structures of NPCs have been challenging to identify by the scientific community. With the development of cryo-electron microscopy and advanced sampling techniques, researchers have made significant progress in understanding the structures of NPCs. This review aims to summarize the latest research on the structural aspects of NPCs and their roles in cardiac physiology and pathology, increase the understanding of the intricate mechanisms of NPC actions, provide valuable insights into the pathogenesis of heart diseases and describe the development of potential novel therapeutic strategies.
    Keywords:  development; diseases; heart; mechanism; nuclear pore complex
    DOI:  https://doi.org/10.31083/j.fbl2812350
  3. Ann Clin Transl Neurol. 2023 Dec 29.
    Nuclear pore pathology underlying multisystem proteinopathy type 3-related inclusion body myopathy.
    Rumiko Izumi, Kensuke Ikeda, Tetsuya Niihori, Naoki Suzuki, Matsuyuki Shirota, Ryo Funayama, Keiko Nakayama, Hitoshi Warita, Maki Tateyama, Yoko Aoki, Masashi Aoki.
       OBJECTIVE: Multisystem proteinopathy type 3 (MSP3) is an inherited, pleiotropic degenerative disorder caused by a mutation in heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), which can affect the muscle, bone, and/or nervous system. This study aimed to determine detailed histopathological features and transcriptomic profile of HNRNPA1-mutated skeletal muscles to reveal the core pathomechanism of hereditary inclusion body myopathy (hIBM), a predominant phenotype of MSP3.
    METHODS: Histopathological analyses and RNA sequencing of HNRNPA1-mutated skeletal muscles harboring a c.940G > A (p.D314N) mutation (NM_031157) were performed, and the results were compared with those of HNRNPA1-unlinked hIBM and control muscle tissues.
    RESULTS: RNA sequencing revealed aberrant alternative splicing events that predominantly occurred in myofibril components and mitochondrial respiratory complex. Enrichment analyses identified the nuclear pore complex (NPC) and nucleocytoplasmic transport as suppressed pathways. These two pathways were linked by the hub genes NUP50, NUP98, NUP153, NUP205, and RanBP2. In immunohistochemistry, these nucleoporin proteins (NUPs) were mislocalized to the cytoplasm and aggregated mostly with TAR DNA-binding protein 43 kDa and, to a lesser extent, with hnRNPA1. Based on ultrastructural observation, irregularly shaped myonuclei with deep invaginations were frequently observed in atrophic fibers, consistent with the disorganization of NPCs. Additionally, regarding the expression profiles of overall NUPs, reduced expression of NUP98, NUP153, and RanBP2 was shared with HNRNPA1-unlinked hIBMs.
    INTERPRETATION: The shared subset of altered NUPs in amyotrophic lateral sclerosis (ALS), as demonstrated in prior research, HNRNPA1-mutated, and HNRNPA1-unlinked hIBM muscle tissues may provide evidence regarding the underlying common nuclear pore pathology of hIBM, ALS, and MSP.
    DOI:  https://doi.org/10.1002/acn3.51977
  4. bioRxiv. 2023 Dec 13. pii: 2023.12.12.571299. [Epub ahead of print]
    Highly variable molecular signatures of TDP-43 loss of function are associated with nuclear pore complex injury in a population study of sporadic ALS patient iPSNs.
    Jeffrey D Rothstein, Caroline Warlick, Alyssa N Coyne.
      The nuclear depletion and cytoplasmic aggregation of the RNA binding protein TDP-43 is widely considered a pathological hallmark of Amyotrophic Lateral Sclerosis (ALS) and related neurodegenerative diseases. Recent studies have artificially reduced TDP-43 in wildtype human neurons to replicate loss of function associated events. Although this prior work has defined a number of gene expression and mRNA splicing changes that occur in a TDP-43 dependent manner, it is unclear how these alterations relate to authentic ALS where TDP-43 is not depleted from the cell but miscompartmentalized to variable extents. Here, in this population study, we generate ∼30,000 qRT-PCR data points spanning 20 genes in induced pluripotent stem cell (iPSC) derived neurons (iPSNs) from >150 control, C9orf72 ALS/FTD, and sALS patients to examine molecular signatures of TDP-43 dysfunction. This data set defines a time dependent and variable profile of individual molecular hallmarks of TDP-43 loss of function within and amongst individual patient lines. Importantly, nearly identical changes are observed in postmortem CNS tissues obtained from a subset of patients whose iPSNs were examined. Notably, these studies provide evidence that induction of nuclear pore complex (NPC) injury via reduction of the transmembrane Nup POM121 in wildtype iPSNs is sufficient to phenocopy disease associated signatured of TDP-43 loss of function thereby directly linking NPC integrity to TDP-43 loss of function. Therapeutically, we demonstrate that the expression of all mRNA species associated with TDP-43 loss of function can be restored in sALS iPSNs via two independent methods to repair NPC injury. Collectively, this data 1) represents a substantial resource for the community to examine TDP-43 loss of function events in authentic sALS patient iPSNs, 2) demonstrates that patient derived iPSNs can accurately reflect actual TDP-43 associated alterations in patient brain, and 3) that targeting NPC injury events can be preclinically and reliably accomplished in an iPSN based platform of a sporadic disease.
    DOI:  https://doi.org/10.1101/2023.12.12.571299
  5. Cell Death Dis. 2024 Jan 04. 15(1): 7
    Nuclear pore protein POM121 regulates subcellular localization and transcriptional activity of PPARγ.
    Yanxiong Yu, Mohammad S Farooq, Sabine Eberhart Meessen, Yidan Jiang, Dominik Kato, Tianzuo Zhan, Christel Weiss, Rony Seger, Wei Kang, Xiang Zhang, Jun Yu, Matthias P A Ebert, Elke Burgermeister.
      Manipulation of the subcellular localization of transcription factors by preventing their shuttling via the nuclear pore complex (NPC) emerges as a novel therapeutic strategy against cancer. One transmembrane component of the NPC is POM121, encoded by a tandem gene locus POM121A/C on chromosome 7. Overexpression of POM121 is associated with metabolic diseases (e.g., diabetes) and unfavorable clinical outcome in patients with colorectal cancer (CRC). Peroxisome proliferator-activated receptor-gamma (PPARγ) is a transcription factor with anti-diabetic and anti-tumoral efficacy. It is inhibited by export from the nucleus to the cytosol via the RAS-RAF-MEK1/2-ERK1/2 signaling pathway, a major oncogenic driver of CRC. We therefore hypothesized that POM121 participates in the transport of PPARγ across the NPC to regulate its transcriptional activity on genes involved in metabolic and tumor control. We found that POM121A/C mRNA was enriched and POM121 protein co-expressed with PPARγ in tissues from CRC patients conferring poor prognosis. Its interactome was predicted to include proteins responsible for tumor metabolism and immunity, and in-silico modeling provided insights into potential 3D structures of POM121. A peptide region downstream of the nuclear localization sequence (NLS) of POM121 was identified as a cytoplasmic interactor of PPARγ. POM121 positivity correlated with the cytoplasmic localization of PPARγ in patients with KRAS mutant CRC. In contrast, POM121A/C silencing by CRISPR/Cas9 sgRNA or siRNA enforced nuclear accumulation of PPARγ and activated PPARγ target genes promoting lipid metabolism and cell cycle arrest resulting in reduced proliferation of human CRC cells. Our data suggest the POM121-PPARγ axis as a potential drugable target in CRC.
    DOI:  https://doi.org/10.1038/s41419-023-06371-1
  6. FEBS Lett. 2023 Dec 29.
    Structural determinants of phosphorylation-dependent nuclear transport of HCMV DNA polymerase processivity factor UL44.
    Emily M Cross, Oriano Marin, Daryl Ariawan, David Aragão, Giorgio Cozza, Enzo Di Iorio, Jade K Forwood, Gualtiero Alvisi.
      Human cytomegalovirus (HCMV) DNA polymerase processivity factor UL44 is transported into the nucleus by importin (IMP) α/β through a classical nuclear localization signal (NLS), and this region is susceptible to cdc2-mediated phosphorylation at position T427. Whilst phosphorylation within and close to the UL44 NLS regulates nuclear transport, the details remain elusive, due to the paucity of structural information regarding the role of negatively charged cargo phosphate groups. We addressed this issue, studying the effect of UL44 T427 phosphorylation on interaction with several IMPα isoforms by biochemical and structural approaches. Phosphorylation decreased UL44/IMPα affinity 10-fold, and a comparative structural analysis of UL44 NLS phosphorylated and non-phosphorylated peptides complexed with mouse IMPα2 revealed the structural rearrangements responsible for phosphorylation-dependent inhibition of UL44 nuclear import.
    Keywords:  DNA polymerase; HCMV; IMP; NLS; PAP; accessory protein; importins; nuclear transport; phosphorylation; regulation
    DOI:  https://doi.org/10.1002/1873-3468.14797
  7. Mol Neurobiol. 2024 Jan 05.
    Fluvoxamine Exerts Sigma-1R to Rescue Autophagy via Pom121-Mediated Nucleocytoplasmic Transport of TFEB.
    Chun-Yu Lin, Hsiang-En Wu, Eddie Feng-Ju Weng, Hsuan-Cheng Wu, Tsung-Ping Su, Shao-Ming Wang.
      Expansion of the GGGGCC-RNA repeat is a known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which currently have no cure. Recent studies have indicated the activation of Sigma-1 receptor plays an important role in providing neuroprotection, especially in ALS and Alzheimer's disease. Nevertheless, the mechanisms underlying Sigma-1R activation and its effect on (G4C2)n-RNA-induced cell death remain unclear. In this study, we demonstrated that fluvoxamine is a Sigma-1R agonist that can increase chaperone activity and stabilize the protein expression of Pom121 in (G4C2)31-RNA-expressing NSC34 cells, leading to increased colocalization at the nuclear envelope. Interestingly, fluvoxamine treatment increased Pom121 protein expression without affecting transcription. In C9orf72-ALS, the nuclear translocation of TFEB autophagy factor decreased owing to nucleocytoplasmic transport defects. Our results showed that pretreatment of NSC34 cells with fluvoxamine promoted the shuttling of TFEB into the nucleus and elevated the expression of LC3-II compared to the overexpression of (G4C2)31-RNA alone. Additionally, even when used alone, fluvoxamine increases Pom121 expression and TFEB translocation. To summarize, fluvoxamine may act as a promising repurposed medicine for patients with C9orf72-ALS, as it stabilizes the nucleoporin Pom121 and promotes the translocation of TFEB in (G4C2)31-RNA-expressing NSC34 cells.
    Keywords:  C9orf72-amyotrophic lateral sclerosis; Fluvoxamine; Nucleocytoplasmic transport; Nucleoporin Pom121; Sigma-1 receptor
    DOI:  https://doi.org/10.1007/s12035-023-03885-9
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