Stress Granule Assembly Disrupts Nucleocytoplasmic Transport

Zhang, Ke; Daigle, J. Gavin; Cunningham, Kathleen M.; Coyne, Alyssa N.; Ruan, Kai; Grima, Jonathan C.; Bowen, Kelly; Wadhwa, Harsh; Yang, Peiguo; Rigo, Frank; Taylor, J. Paul; Gitler, Aaron D.; Rothstein, Jeffrey D.; Lloyd, Thomas E.

doi:10.1016/j.cell.2018.03.025

Cited by 325 publications

(389 citation statements)

References 63 publications

(115 reference statements)

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“…In cells with reduced nuclear import, we observed cytoplasmic lamin accumulation, suggesting that relatively high lamin import kinetics are necessary to avoid cytoplasmic aggregation. These lamin aggregates could be relevant to disease states where nuclear import is compromised [91][92][93][94][95], laminopathies [96][97][98][99][100][101][102], or cellular stress [103]. ELYS is a multifunctional protein which has been shown to interact with chromatin, enhancers, and promoters [53, 104,105].…”

Section: Discussionmentioning

confidence: 99%

The nucleoporin ELYS regulates nuclear size by controlling NPC number and nuclear import capacity

et al. 2019

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How intracellular organelles acquire their characteristic sizes is a fundamental question in cell biology. Given stereotypical changes in nuclear size in cancer, it is important to understand the mechanisms that control nuclear size in human cells. Using a high‐throughput imaging RNAi screen, we identify and mechanistically characterize ELYS, a nucleoporin required for post‐mitotic nuclear pore complex (NPC) assembly, as a determinant of nuclear size in mammalian cells. ELYS knockdown results in small nuclei, reduced nuclear lamin B2 localization, lower NPC density, and decreased nuclear import. Increasing nuclear import by importin α overexpression rescues nuclear size and lamin B2 import, while inhibiting importin α/β‐mediated nuclear import decreases nuclear size. Conversely, ELYS overexpression increases nuclear size, enriches nuclear lamin B2 at the nuclear periphery, and elevates NPC density and nuclear import. Consistent with these observations, knockdown or inhibition of exportin 1 increases nuclear size. Thus, we identify ELYS as a novel positive effector of mammalian nuclear size and propose that nuclear size is sensitive to NPC density and nuclear import capacity.

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Section: Discussionmentioning

confidence: 99%

The nucleoporin ELYS regulates nuclear size by controlling NPC number and nuclear import capacity

et al. 2019

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“…It remains to be determined whether this is caused by age dependent leaky nuclear pores or other cellular stresses, less robust disassembly of cytoplasmic RNA stress granules or accumulation of free radicals. Recently, it has been shown that nuclear pore components associate with RNA stress granules during cellular stress, bolstering the role of cytoplasmic granules in ALS/FTD (Zhang et al, 2018). Thus it would appear that the presence and persistence of TDP-43 containing granules in the cytoplasm provides opportunities for failure of ribostasis through RNA sequestration and translation inhibition, and proteostasis through aggregate formation, both of which correlate with degeneration and death.…”

Section: Discussionmentioning

confidence: 99%

Dynamic duo – FMRP and TDP-43: Regulating common targets, causing different diseases

2018

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RNA binding proteins play essential roles during development and aging, and are also involved in disease pathomechanisms. RNA sequencing and omics analyses have provided a window into systems level alterations in neurological disease, and have identified RNA processing defects among notable disease mechanisms. This review focuses on two seemingly distinct neurological disorders, the RNA binding proteins they are linked to, and their newly discovered functional relationship. When deficient, Fragile X Mental Retardation Protein (FMRP) causes developmental deficits and autistic behaviors while TAR-DNA Binding Protein (TDP-43) dysregulation causes age dependent neuronal degeneration. Recent findings that FMRP and TDP-43 associate in ribonuclear protein particles and share mRNA targets in neurons highlight the critical importance of translation regulation in synaptic plasticity and provide new perspectives on neuronal vulnerability during lifespan.

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“…The resulting ribosome‐free mRNAs and associated RNA‐binding proteins, translation initiation factors and the 40S ribosomal subunit localize to SGs (Figure B). In addition to translational machinery, numerous proteins involved in RNA processing and nuclear transport are recruited to SGs . Both RNA and SG proteins undergo phase separation, although how these processes are coordinated to assemble SGs remains an open question.…”

Section: Biomolecular Condensates In Neurodegenerationmentioning

confidence: 99%

Biomolecular condensates in neurodegeneration and cancer

Spannl

Tereshchenko

Mastromarco

et al. 2019

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The intracellular environment is partitioned into functionally distinct compartments containing specific sets of molecules and reactions. Biomolecular condensates, also referred to as membrane‐less organelles, are diverse and abundant cellular compartments that lack membranous enclosures. Molecules assemble into condensates by phase separation; multivalent weak interactions drive molecules to separate from their surroundings and concentrate in discrete locations. Biomolecular condensates exist in all eukaryotes and in some prokaryotes, and participate in various essential house‐keeping, stress‐response and cell type‐specific processes. An increasing number of recent studies link abnormal condensate formation, composition and material properties to a number of disease states. In this review, we discuss current knowledge and models describing the regulation of condensates and how they become dysregulated in neurodegeneration and cancer. Further research on the regulation of biomolecular phase separation will help us to better understand their role in cell physiology and disease.

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Stress Granule Assembly Disrupts Nucleocytoplasmic Transport

Cited by 325 publications

References 63 publications

The nucleoporin ELYS regulates nuclear size by controlling NPC number and nuclear import capacity

The nucleoporin ELYS regulates nuclear size by controlling NPC number and nuclear import capacity

Dynamic duo – FMRP and TDP-43: Regulating common targets, causing different diseases

Biomolecular condensates in neurodegeneration and cancer

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