bims-nucpor Biomed News
on Nuclear pore complex and nucleoporins in stress, aging and disease
Issue of 2023–03–05
seven papers selected by
Sara Mingu, Johannes Gutenberg University
  1. Mechanisms of Nuclear Pore Complex disassembly by the mitotic Polo-Like Kinase 1 (PLK-1) in C. elegans embryos.
  2. An evolutionarily conserved bimodular domain anchors ZC3HC1 and its yeast homolog Pml39p to the nuclear basket.
  3. Case report: Compound heterozygous NUP85 variants cause autosomal recessive primary microcephaly.
  4. Importin alpha family NAAT/IBB domain: Functions of a pleiotropic long chameleon sequence.
  5. Overexpressed Nup88 stabilized through interaction with Nup62 promotes NF-κB dependent pathways in cancer.
  6. Plant pathogens and symbionts target the plant nucleus.
  7. Characterization of the nuclear import of human CHD4-NuRD complex.
  1. bioRxiv. 2023 Feb 22. pii: 2023.02.21.528438. [Epub ahead of print]
    Mechanisms of Nuclear Pore Complex disassembly by the mitotic Polo-Like Kinase 1 (PLK-1) in C. elegans embryos.
    Sylvia Nkombo Nkoula, Griselda Velez-Aguilera, Batool Ossareh-Nazari, Lucie Van Hove, Cristina Ayuso, Véronique Legros, Guillaume Chevreux, Laura Thomas, Géraldine Seydoux, Peter Askjaer, Lionel Pintard.
      The nuclear envelope, which protects and organizes the interphase genome, is dismantled during mitosis. In the C. elegans zygote, nuclear envelope breakdown (NEBD) of the parental pronuclei is spatially and temporally regulated during mitosis to promote the unification of the parental genomes. During NEBD, Nuclear Pore Complex (NPC) disassembly is critical for rupturing the nuclear permeability barrier and removing the NPCs from the membranes near the centrosomes and between the juxtaposed pronuclei. By combining live imaging, biochemistry, and phosphoproteomics, we characterized NPC disassembly and unveiled the exact role of the mitotic kinase PLK-1 in this process. We show that PLK-1 disassembles the NPC by targeting multiple NPC sub-complexes, including the cytoplasmic filaments, the central channel, and the inner ring. Notably, PLK-1 is recruited to and phosphorylates intrinsically disordered regions of several multivalent linker nucleoporins, a mechanism that appears to be an evolutionarily conserved driver of NPC disassembly during mitosis. (149/150 words).
    One-Sentence Summary: PLK-1 targets intrinsically disordered regions of multiple multivalent nucleoporins to dismantle the nuclear pore complexes in the C. elegans zygote.
    DOI:  https://doi.org/10.1101/2023.02.21.528438
  2. Mol Biol Cell. 2023 Mar 01. mbcE22090402
    An evolutionarily conserved bimodular domain anchors ZC3HC1 and its yeast homolog Pml39p to the nuclear basket.
    Philip Gunkel, Haruki Iino, Sandra Krull, Volker C Cordes.
      The proteins ZC3HC1 and TPR are structural components of the nuclear basket (NB), a fibrillar structure attached to the nucleoplasmic side of the nuclear pore complex (NPC). ZC3HC1 initially binds to the NB in a TPR-dependent manner and can subsequently recruit additional TPR polypeptides to this structure. Here, we examined the molecular properties of ZC3HC1 that enable its initial binding to the NB and TPR. We report the identification and definition of a nuclear basket-interaction domain (NuBaID) of HsZC3HC1 that comprises two similarly built modules, both essential for binding the NB-resident TPR. We show that such a bimodular construction is evolutionarily conserved, which we further investigated in Dictyostelium discoideum and Saccharomyces cerevisiae. Presenting ScPml39p as the ZC3HC1 homolog in budding yeast, we show that the bimodular NuBaID of Pml39p is essential for binding to the yeast NB and its TPR homologs ScMlp1p and ScMlp2p, and we further demonstrate that Pml39p enables linkage between subpopulations of Mlp1p. We eventually delineate the common NuBaID of the human, amoebic, and yeast homolog as the defining structural entity of a unique protein not found in all but likely present in most taxa of the eukaryotic realm.
    DOI:  https://doi.org/10.1091/mbc.E22-09-0402
  3. Front Neurol. 2023 ;14 1124886
    Case report: Compound heterozygous NUP85 variants cause autosomal recessive primary microcephaly.
    Ethiraj Ravindran, Gaetan Lesca, Louis Januel, Linus Goldgruber, Achim Dickmanns, Henri Margot, Angela M Kaindl.
      Nucleoporin (NUP) 85 is a member of the Y-complex of nuclear pore complex (NPC) that is key for nucleocytoplasmic transport function, regulation of mitosis, transcription, and chromatin organization. Mutations in various nucleoporin genes have been linked to several human diseases. Among them, NUP85 was linked to childhood-onset steroid-resistant nephrotic syndrome (SRNS) in four affected individuals with intellectual disability but no microcephaly. Recently, we broaden the phenotype spectrum of NUP85-associated disease by reporting NUP85 variants in two unrelated individuals with primary autosomal recessive microcephaly (MCPH) and Seckel syndrome (SCKS) spectrum disorders (MCPH-SCKS) without SRNS. In this study, we report compound heterozygous NUP85 variants in an index patient with only MCPH phenotype, but neither Seckel syndrome nor SRNS was reported. We showed that the identified missense variants cause reduced cell viability of patient-derived fibroblasts. Structural simulation analysis of double variants is predicted to alter the structure of NUP85 and its interactions with neighboring NUPs. Our study thereby further expands the phenotypic spectrum of NUP85-associated human disorder and emphasizes the crucial role of NUP85 in the brain development and function.
    Keywords:  MCPH-SCKS; NUP85; brain development; microcephaly; speech disorder
    DOI:  https://doi.org/10.3389/fneur.2023.1124886
  4. Adv Protein Chem Struct Biol. 2023 ;pii: S1876-1623(22)00094-3. [Epub ahead of print]134 175-209
    Importin alpha family NAAT/IBB domain: Functions of a pleiotropic long chameleon sequence.
    Kazuya Jibiki, Takashi S Kodama, Noriko Yasuhara.
      Nuclear transport is essential for eukaryotic cell survival and regulates the movement of functional molecules in and out of the nucleus via the nuclear pore. Transport is facilitated by protein-protein interactions between cargo and transport receptors, which contribute to the expression and regulation of downstream genetic information. This chapter focuses on the molecular basis of the multifunctional nature of the importin α family, the representative transport receptors that bring proteins into the nucleus. Importin α performs multiple functions during the nuclear transport cycle through interactions with multiple molecules by a single domain called the IBB domain. This domain is a long chameleon sequence, which can change its conformation and binding mode depending on the interaction partners. By considering the evolutionarily conserved biochemical/physicochemical propensities of the amino acids constituting the functional complex interfaces, together with their structural properties, the mechanisms of switching between multiple complexes formed via IBB and the regulation of downstream functions are examined in detail. The mechanism of regulation by IBB indicates that the time has come for a paradigm shift in the way we view the molecular mechanisms by which proteins regulate downstream functions through their interactions with other molecules.
    Keywords:  Biochemical/physicochemical propensity; Chameleon sequence; IBB domain; Importin α; Multifunctional domain; NAAT domain; Nuclear transport
    DOI:  https://doi.org/10.1016/bs.apcsb.2022.11.005
  5. Front Oncol. 2023 ;13 1095046
    Overexpressed Nup88 stabilized through interaction with Nup62 promotes NF-κB dependent pathways in cancer.
    Usha Singh, Divya Bindra, Atul Samaiya, Ram Kumar Mishra.
      Bidirectional nucleo-cytoplasmic transport, regulating several vital cellular processes, is mediated by the Nuclear Pore Complex (NPC) comprising the nucleoporin (Nup) proteins. Nup88, a constituent nucleoporin, is overexpressed in many cancers, and a positive correlation exists between progressive stages of cancer and Nup88 levels. While a significant link of Nup88 overexpression in head and neck cancer exists but mechanistic details of Nup88 roles in tumorigenesis are sparse. Here, we report that Nup88 and Nup62 levels are significantly elevated in head and neck cancer patient samples and cell lines. We demonstrate that the elevated levels of Nup88 or Nup62 impart proliferation and migration advantages to cells. Interestingly, Nup88-Nup62 engage in a strong interaction independent of Nup-glycosylation status and cell-cycle stages. We report that the interaction with Nup62 stabilizes Nup88 by inhibiting the proteasome-mediated degradation of overexpressed Nup88. Overexpressed Nup88 stabilized by interaction with Nup62 can interact with NF-κB (p65) and sequesters p65 partly into nucleus of unstimulated cells. NF-κB targets like Akt, c-myc, IL-6 and BIRC3 promoting proliferation and growth are induced under Nup88 overexpression conditions. In conclusion, our data indicates that simultaneous overexpression of Nup62 and Nup88 in head and neck cancer stabilizes Nup88. Stabilized Nup88 interacts and activates p65 pathway, which perhaps is the underlying mechanism in Nup88 overexpressing tumors.
    Keywords:  NFkB; Nup62; Nup88; head and neck cancer; nucleoporins (NUPs)
    DOI:  https://doi.org/10.3389/fonc.2023.1095046
  6. Curr Opin Microbiol. 2023 Mar 01. pii: S1369-5274(23)00021-8. [Epub ahead of print]72 102284
    Plant pathogens and symbionts target the plant nucleus.
    Neda Tehrani, Raka M Mitra.
      In plant-microbe interactions, symbionts and pathogens live within plants and attempt to avoid triggering plant defense responses. In order to do so, these microbes have evolved multiple mechanisms that target components of the plant cell nucleus. Rhizobia-induced symbiotic signaling requires the function of specific legume nucleoporins within the nuclear pore complex. Symbiont and pathogen effectors harbor nuclear localization sequences that facilitate movement across nuclear pores, allowing these proteins to target transcription factors that function in defense. Oomycete pathogens introduce proteins that interact with plant pre-mRNA splicing components in order to alter host splicing of defense-related transcripts. Together, these functions indicate that the nucleus is an active site of symbiotic and pathogenic functioning in plant-microbe interactions.
    DOI:  https://doi.org/10.1016/j.mib.2023.102284
  7. J Cell Sci. 2023 Mar 02. pii: jcs.260724. [Epub ahead of print]
    Characterization of the nuclear import of human CHD4-NuRD complex.
    Helen Hoffmeister, Simon Holzinger, Marie-Sofie Dürr, Astrid Bruckmann, Susanne Schindler, Regina Gröbner-Ferreira, Reinhard Depping, Gernot Längst.
      Chromatin remodeling enzymes form large multiprotein complexes that play central roles in regulating access to the genome. Here, we characterize the nuclear import of the human CHD4 protein. We show that CHD4 enters the nucleus by means of several importin alpha proteins (1, 5, 6, and 7), and rather independently of importin beta 1. Importin alpha 1 directly interacts with a monopartite "KRKR"-motif in the N-terminus of CHD4 (aa 304-307). However, alanine mutagenesis of this motif only leads to approx. 50% reduction in nuclear localization of CHD4, implying additional import mechanisms. Interestingly, we can show that CHD4 is already associated with NuRD core subunits such as MTA2, HDAC1, or RbAp46 in the cytoplasm, suggesting an assembly of the NuRD core complex before nuclear import. We propose that, in addition to the importin-alpha-dependent nuclear localization signal, CHD4 is dragged into the nucleus by a "piggyback mechanism" using the import signals of the associated NuRD subunits.
    Keywords:  Chromatin remodeling; NuRD; Nuclear import
    DOI:  https://doi.org/10.1242/jcs.260724
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