Interactions between non‐structured domains of FG‐ and non‐FG‐nucleoporins coordinate the ordered assembly of the nuclear pore complex in mitosis

Konishi, Hide A.; Yoshimura, Shige H.

doi:10.1096/fj.201901669r

Cited by 11 publications

(8 citation statements)

References 31 publications

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“…Many in vitro and in vivo experiments suggest that the IDR regions of Nups form a selective barrier based on a phase-separation mechanism in the NPC (Celetti et al, 2020;Frey and Gö rlich, 2007;Frey et al, 2006;Konishi et al, 2017;Konishi and Yoshimura, 2020). However, most of the cysteine residues found to be involved in crowding control in this study were localized in structured (non-IDR) regions of Nups ( Figure 3A).…”

Section: Proximal Control Model Of Molecular Crowding In Vivomentioning

confidence: 63%

Redox-Sensitive Cysteines Confer Proximal Control of the Molecular Crowding Barrier in the Nuclear Pore

et al. 2020

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Section: Proximal Control Model Of Molecular Crowding In Vivomentioning

confidence: 63%

Redox-Sensitive Cysteines Confer Proximal Control of the Molecular Crowding Barrier in the Nuclear Pore

et al. 2020

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“…These highly enriched Nups comprised phenylalanine-glycine (FG)-rich Nups of the human NPC 39 (Figure 1D and 1F). This was a striking observation because FG-Nups can assemble into hydrogels and biomolecular condensates, a property shared with inner ring Nup NUP35 [40][41][42][43] .…”

Section: Mx2 Interacts With Fg-rich Nucleoporins and Granule-associat...mentioning

confidence: 94%

MX2 restricts HIV-1 and herpes simplex virus type 1 by forming cytoplasmic biomolecular condensates that mimic nuclear pore complexes

Moschonas,

Delhaye,

Cooreman

et al. 2023

Preprint

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Human myxovirus resistance 2 (MX2) can potently restrict HIV-1 and herpesviruses at a post-entry step by a process that requires MX2 interaction with the capsids of these viruses. The involvement of other host cell factors in this process, however, remains poorly understood. Here, we mapped the proximity interactome of MX2 revealing strong enrichment of phenylalanine-glycine (FG)-rich proteins related to the nuclear pore complex as well as proteins that are part of cytoplasmic ribonucleoprotein granules. MX2 interacts with these proteins to form multiprotein cytoplasmic biomolecular condensates that are essential for its anti-HIV-1 and -herpes simplex virus-1 (HSV-1) activity. MX2 condensate formation requires the disordered N-terminal region of MX2 and its dimerization. We also demonstrate that incoming HIV-1 and HSV-1 capsids associate with MX2 at dynamic cytoplasmic biomolecular condensates. Our results reveal that MX2 forms nuclear pore-mimicking cytoplasmic condensates that act as nuclear pore decoys, thereby interfering with nuclear entry of HIV-1 and HSV-1.

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“…Hexahistidine (His 6 )-tagged proteins (TDP-CTF and Nup62FG) were purified as described previously [24]. E. coli cells (BL21-CodonPlus(DE3)-RIL, Agilent Technologies) harbouring the expression vector for His 6 -tagged IDRs were cultured in Luria-Bertani medium.…”

Section: Recombinant Protein Purificationmentioning

confidence: 99%

Nuclear import receptors are recruited by FG-nucleoporins to rescue hallmarks of TDP-43 proteinopathy

Khalil

Chhangani

Wren

et al. 2022

Mol Neurodegeneration

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Background Cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) disease spectrum, causing both nuclear loss-of-function and cytoplasmic toxic gain-of-function phenotypes. While TDP-43 proteinopathy has been associated with defects in nucleocytoplasmic transport, this process is still poorly understood. Here we study the role of karyopherin-β1 (KPNB1) and other nuclear import receptors in regulating TDP-43 pathology. Methods We used immunostaining, immunoprecipitation, biochemical and toxicity assays in cell lines, primary neuron and organotypic mouse brain slice cultures, to determine the impact of KPNB1 on the solubility, localization, and toxicity of pathological TDP-43 constructs. Postmortem patient brain and spinal cord tissue was stained to assess KPNB1 colocalization with TDP-43 inclusions. Turbidity assays were employed to study the dissolution and prevention of aggregation of recombinant TDP-43 fibrils in vitro. Fly models of TDP-43 proteinopathy were used to determine the effect of KPNB1 on their neurodegenerative phenotype in vivo. Results We discovered that several members of the nuclear import receptor protein family can reduce the formation of pathological TDP-43 aggregates. Using KPNB1 as a model, we found that its activity depends on the prion-like C-terminal region of TDP-43, which mediates the co-aggregation with phenylalanine and glycine-rich nucleoporins (FG-Nups) such as Nup62. KPNB1 is recruited into these co-aggregates where it acts as a molecular chaperone that reverses aberrant phase transition of Nup62 and TDP-43. These findings are supported by the discovery that Nup62 and KPNB1 are also sequestered into pathological TDP-43 aggregates in ALS/FTD postmortem CNS tissue, and by the identification of the fly ortholog of KPNB1 as a strong protective modifier in Drosophila models of TDP-43 proteinopathy. Our results show that KPNB1 can rescue all hallmarks of TDP-43 pathology, by restoring its solubility and nuclear localization, and reducing neurodegeneration in cellular and animal models of ALS/FTD. Conclusion Our findings suggest a novel NLS-independent mechanism where, analogous to its canonical role in dissolving the diffusion barrier formed by FG-Nups in the nuclear pore, KPNB1 is recruited into TDP-43/FG-Nup co-aggregates present in TDP-43 proteinopathies and therapeutically reverses their deleterious phase transition and mislocalization, mitigating neurodegeneration. Graphical Abstract

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Interactions between non‐structured domains of FG‐ and non‐FG‐nucleoporins coordinate the ordered assembly of the nuclear pore complex in mitosis

Cited by 11 publications

References 31 publications

Redox-Sensitive Cysteines Confer Proximal Control of the Molecular Crowding Barrier in the Nuclear Pore

Redox-Sensitive Cysteines Confer Proximal Control of the Molecular Crowding Barrier in the Nuclear Pore

MX2 restricts HIV-1 and herpes simplex virus type 1 by forming cytoplasmic biomolecular condensates that mimic nuclear pore complexes

Nuclear import receptors are recruited by FG-nucleoporins to rescue hallmarks of TDP-43 proteinopathy

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