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

Zhang, Jian Guo; Watanabe, Rikiya; Konishi, Hide A.; Fujiwara, Takeshi; Yoshimura, Shige H.; Kumeta, Masahiro

doi:10.1016/j.celrep.2020.108484

Cited by 4 publications

(4 citation statements)

References 51 publications

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“…Furthermore, exogenously supplied reducing agent can induce pharyngeal cuticle apolysis during the intermolt period ( Stenvall et al, 2011 ). Manipulating the redox state of cysteines can alter the ability of IDR-rich proteins to phase separate or further condense ( Reed and Hammer, 2018 ; Zhang et al, 2020 ; Kato et al, 2019 ). Whether the abundant cysteines within the pharyngeal cuticle are key to phase separation and yield a network of variably dynamic cross-linked proteins remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

A spatiotemporal reconstruction of the C. elegans pharyngeal cuticle reveals a structure rich in phase-separating proteins

Kamal

Tokmakjian

Knox

et al. 2022

eLife

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How the cuticles of the roughly 4.5 million species of ecdysozoan animals are constructed is not well understood. Here, we systematically mine gene expression datasets to uncover the spatiotemporal blueprint for how the chitin-based pharyngeal cuticle of the nematode Caenorhabditis elegans is built. We demonstrate that the blueprint correctly predicts expression patterns and functional relevance to cuticle development. We find that as larvae prepare to molt, catabolic enzymes are upregulated and the genes that encode chitin synthase, chitin cross-linkers, and homologs of amyloid regulators subsequently peak in expression. 48% of the gene products secreted during the molt are predicted to be intrinsically disordered proteins (IDPs), many of which belong to four distinct families whose transcripts are expressed in overlapping waves. These include the IDPAs, IDPBs, and IDPCs, which are introduced for the first time here. All four families have sequence properties that drive phase separation and we demonstrate phase-separation for one exemplar in vitro. This systematic analysis represents the first blueprint for cuticle construction and highlights the massive contribution that phase-separating materials make to the structure.

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Section: Discussionmentioning

confidence: 99%

A spatiotemporal reconstruction of the C. elegans pharyngeal cuticle reveals a structure rich in phase-separating proteins

Kamal

Tokmakjian

Knox

et al. 2022

eLife

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“…Finally, oxidative stress promotes phase transitions of proteins by causing declines in solubility and degradation of proteins that are prone to form intracellular aggregates [79,80]. In particular, components of the nucleocytoplasmic machinery are highly susceptible to oxidative stress as a result of modifications of components of nucleocytoplasmic transport by reactive oxygen species [81–89]. In spite of these advances, the pathomechanisms and pathophysiological underpinnings arising from selective disturbances of interactions between nucleoporins, nuclear transport receptors and client substrates in neurodegeneration remain poorly understood.…”

Section: Nucleocytoplasmic Transport In Phase Transitions and Neurode...mentioning

confidence: 99%

“…Oxidative stress promotes disturbances in phase transitions by declines in solubility and degradation of proteins, and by impairments of protein interactions owing to distinct propensities of protein ensembles to modifications by reactive oxygen species [79,80]. Specifically, nucleocytoplasmic transport and components of the Ranbp2 ensemble are highly susceptible to oxidative stress [81–89]. Our prior studies have shown that haploinsufficiency of Ranbp2 in inbred mice neither causes overt morphological impairments to retinal neurons, such as photoreceptors, nor affects photoreceptor survival when mice are reared under cyclic and low illuminance [150].…”

Section: Suppression Of Pathologies Linked To Oxidative Stress By Ran...mentioning

confidence: 99%

Nucleocytoplasmic transport at the crossroads of proteostasis, neurodegeneration and neuroprotection

Ferreira

2023

FEBS Letters

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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.

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“…Furthermore, exogenously supplied reducing agent can induce pharyngeal cuticle apolysis during the intermolt period (67). Manipulating the redox state of cysteines can alter the ability of IDR-rich proteins to phase-separate or further condense (68)(69)(70). Whether the abundant cysteines within the pharyngeal cuticle are key to phase separation and yield a network of variably dynamic cross-linked proteins remains to be determined.…”

Section: Destructionmentioning

confidence: 99%

A Spatiotemporal Reconstruction of the C. elegans Pharyngeal Cuticle Reveals a Structure Rich in Phase-Separating Proteins

Kamal

Tokmakjian

Knox

et al. 2022

Preprint

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Roughly 4.5 million species of ecdysozoan animals repeatedly shed their old cuticle and construct a new one underneath to accommodate growth. How cuticles are constructed is not well understood. Here, we systematically mine gene expression datasets to uncover the spatiotemporal blueprint for how the chitin-based pharyngeal cuticle of the nematode Caenorhabditis elegans is built. We demonstrate that the blueprint correctly predicts expression patterns and functional relevance to cuticle development. We find that as larvae prepare to molt, catabolic enzymes are upregulated and the genes that encode chitin synthase, chitin cross-linkers, and homologs of amyloid regulators subsequently peak in expression. 48% of the gene products secreted during the molt are predicted to be intrinsically disordered proteins (IDPs), many of which belong to four distinct families that are expressed in overlapping waves. These include the IDPAs, IDPBs, and IDPCs that are introduced for the first time here. We find that all four families have sequence properties known to drive phase separation and show in vitro phase separation for one of these proteins. This systematic analysis reveals the massive contribution that IDPs make to the cuticle and highlights how reversibly phase-separating materials may facilitate cuticle disassembly and reassembly during the molt.

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

Cited by 4 publications

References 51 publications

A spatiotemporal reconstruction of the C. elegans pharyngeal cuticle reveals a structure rich in phase-separating proteins

A spatiotemporal reconstruction of the C. elegans pharyngeal cuticle reveals a structure rich in phase-separating proteins

Nucleocytoplasmic transport at the crossroads of proteostasis, neurodegeneration and neuroprotection

A Spatiotemporal Reconstruction of the C. elegans Pharyngeal Cuticle Reveals a Structure Rich in Phase-Separating Proteins

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