Nuclear Import Receptors Directly Bind to Arginine-Rich Dipeptide Repeat Proteins and Suppress Their Pathological Interactions

Hutten, Saskia; Usluer, Sinem; Bourgeois, Benjamin; Simonetti, Francesca; Odeh, Hana M.; Fare, Charlotte M.; Czuppa, Mareike; Hruška-Plocháň, Marián; Hofweber, Mario; Polymenidou, Magdalini; Shorter, James; Edbauer, Dieter; Madl, Tobias; Dormann, Dorothee

doi:10.1016/j.celrep.2020.108538

Cited by 84 publications

(147 citation statements)

References 96 publications

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“…As another endogenous mechanism of A1 cluster clearance, TNPO1 may aid in dissociation by shuttling resolved monomeric OptoA1WT back to the nucleus, thereby reducing the local cytoplasmic concentration of OptoA1WT and limiting further self-interactions. This proposed mechanism is supported by a recent study by Hutten et al showing that increasing concentrations of importin proteins inhibits TDP-43 cytoplasmic self-association by transporting it back into the nucleus [66].…”

Section: Discussionmentioning

confidence: 66%

Multiple Sclerosis-Associated hnRNPA1 Mutations Alter hnRNPA1 Dynamics and Influence Stress Granule Formation

Clarke

Thibault

Salapa

et al. 2021

IJMS

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Evidence indicates that dysfunctional heterogeneous ribonucleoprotein A1 (hnRNPA1; A1) contributes to the pathogenesis of neurodegeneration in multiple sclerosis. Understanding molecular mechanisms of neurodegeneration in multiple sclerosis may result in novel therapies that attenuate neurodegeneration, thereby improving the lives of MS patients with multiple sclerosis. Using an in vitro, blue light induced, optogenetic protein expression system containing the optogene Cryptochrome 2 and a fluorescent mCherry reporter, we examined the effects of multiple sclerosis-associated somatic A1 mutations (P275S and F281L) in A1 localization, cluster kinetics and stress granule formation in real-time. We show that A1 mutations caused cytoplasmic mislocalization, and significantly altered the kinetics of A1 cluster formation/dissociation, and the quantity and size of clusters. A1 mutations also caused stress granule formation to occur more quickly and frequently in response to blue light stimulation. This study establishes a live cell optogenetics imaging system to probe localization and association characteristics of A1. It also demonstrates that somatic mutations in A1 alter its function and promote stress granule formation, which supports the hypothesis that A1 dysfunction may exacerbate neurodegeneration in multiple sclerosis.

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Section: Discussionmentioning

confidence: 66%

Multiple Sclerosis-Associated hnRNPA1 Mutations Alter hnRNPA1 Dynamics and Influence Stress Granule Formation

Clarke

Thibault

Salapa

et al. 2021

IJMS

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“…Poorly dynamic stress granules induced by expression of the arginine rich DPRs can sequester both nucleoporins and the transport receptors and thereby disrupt nucleocytoplasmic transport (Zhang et al, 2018a); indeed, transport receptors are known components of physiological stress granules (Chang and Tarn, 2009;Fujimura et al, 2010;Mahboubi et al, 2013). Transport receptor-mediated nuclear import is also impaired by the arginine rich DPRs (Jovičić et al, 2015;Solomon et al, 2018;Hayes et al, 2020;Cook et al, 2020;Hutten et al, 2020). The arginine rich DPRs bind several transport receptors in vitro (Lee et al, 2016;Hutten et al, 2020).…”

Section: Nucleocytoplasmic Transportmentioning

confidence: 99%

“…Transport receptor-mediated nuclear import is also impaired by the arginine rich DPRs (Jovičić et al, 2015;Solomon et al, 2018;Hayes et al, 2020;Cook et al, 2020;Hutten et al, 2020). The arginine rich DPRs bind several transport receptors in vitro (Lee et al, 2016;Hutten et al, 2020). Interaction with importin-β occurs via competition with the binding of arginine rich nuclear localization signals on cargo and thus inhibits their transport (Hayes et al, 2020), whereas polyPR-transportin-1 binding has recently been pinpointed to the nuclear localization recognition domain of transportin-1 (Nanaura et al, 2019, preprint).…”

Section: Nucleocytoplasmic Transportmentioning

confidence: 99%

“…Interaction with importin-β occurs via competition with the binding of arginine rich nuclear localization signals on cargo and thus inhibits their transport (Hayes et al, 2020), whereas polyPR-transportin-1 binding has recently been pinpointed to the nuclear localization recognition domain of transportin-1 (Nanaura et al, 2019, preprint). Arginine rich DPR binding reduces transport receptor solubility and drives their oligomerization and LLPS with transportin-1, importin-α or an importin-α/β complex (as occurs for physiological transport) being more susceptible than importin-β alone to these effects; exportin-1 remained unaffected in solubility and biophysical assays (Hutten et al, 2020). Condensates formed by poly-GR and transportin-1 showed no recovery after photobleaching showing that proteins are immobile in these structures.…”

Section: Nucleocytoplasmic Transportmentioning

confidence: 99%

“…Based on this it has been proposed that TDP-43 mislocalization and/or aggregation are the most likely effectors of toxicity from the C9orf72 mutation (Edbauer and Haass, 2016). Overt TDP-43 pathology is absent in many in vivo models of the C9orf72 mutation (possibly due to the short lifespan of model organisms) but increased cytoplasmic accumulation, increased biochemical insolubility or phosphorylation have been observed in Drosophila, murine and cellular models expressing poly-GR and poly-GA (Khosravi et al, 2017(Khosravi et al, , 2020Schludi et al, 2017;Solomon et al, 2018;Cook et al, 2020;Hutten et al, 2020;LaClair et al, 2020;Park et al, 2020;West et al, 2020). There have also been reports of association between TDP-43 and DPR pathologies: dendritic-like aggregates of poly-GR co-localized almost completely with phosphorylated TDP-43 in C9orf72-ALS motor cortex but formed only a small proportion of these TDP-43 aggregates in total (Saberi et al, 2018); similarly, a proportion of both inclusions of poly-GR and poly-GA have been found to colocalize with TDP-43 in C9orf72-FTD/ALS hippocampus (Cook et al, 2020).…”

Section: Tdp-43 Aggregation and Phase Separationmentioning

confidence: 99%

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Altered Phase Separation and Cellular Impact in C9orf72-Linked ALS/FTD

Solomon

Smikle

Reid

et al. 2021

Front. Cell. Neurosci.

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Since the discovery of the C9orf72 repeat expansion mutation as causative for chromosome 9-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in 2011, a multitude of cellular pathways have been implicated. However, evidence has also been accumulating for a key mechanism of cellular compartmentalization—phase separation. Liquid-liquid phase separation (LLPS) is fundamental for the formation of membraneless organelles including stress granules, the nucleolus, Cajal bodies, nuclear speckles and the central channel of the nuclear pore. Evidence has now accumulated showing that the formation and function of these membraneless organelles is impaired by both the toxic arginine rich dipeptide repeat proteins (DPRs), translated from the C9orf72 repeat RNA transcript, and the repeat RNA itself. Both the arginine rich DPRs and repeat RNA themselves undergo phase separation and disrupt the physiological phase separation of proteins involved in the formation of these liquid-like organelles. Hence abnormal phase separation may explain a number of pathological cellular phenomena associated with C9orf72-ALS/FTD. In this review article, we will discuss the principles of phase separation, phase separation of the DPRs and repeat RNA themselves and how they perturb LLPS associated with membraneless organelles and the functional consequences of this. We will then discuss how phase separation may impact the major pathological feature of C9orf72-ALS/FTD, TDP-43 proteinopathy, and how LLPS may be targeted therapeutically in disease.

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Coordinating nucleoporin condensation and nuclear pore complex assembly

Kuiper,

Prophet,

Schlieker

2023

FEBS Letters

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The nuclear pore complex (NPC) is among the most elaborate protein complexes in eukaryotes. While ribosomes and proteasomes are known to require dedicated assembly machinery, our understanding of NPC assembly is at a relatively early stage. Defects in NPC assembly or homeostasis are tied to movement disorders, including dystonia and amyotrophic lateral sclerosis (ALS), as well as aging, requiring a better understanding of these processes to enable therapeutic intervention. Here, we discuss recent progress in the understanding of NPC assembly and highlight how related defects in human disorders can shed light on NPC biogenesis. We propose that the condensation of phenylalanine‐glycine repeat nucleoporins needs to be carefully controlled during NPC assembly to prevent aberrant condensation, aggregation, or amyloid formation.

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Nuclear Import Receptors Directly Bind to Arginine-Rich Dipeptide Repeat Proteins and Suppress Their Pathological Interactions

Abstract: Highlights d Importins directly bind to arginine-rich dipeptide repeat proteins (R-rich DPRs) d R-rich DPRs induce importin and TDP-43 condensation d Poly-GR impairs TDP-43 nuclear import d Elevated importin levels shield R-rich DPRs from pathological interactions

Cited by 84 publications

References 96 publications

Multiple Sclerosis-Associated hnRNPA1 Mutations Alter hnRNPA1 Dynamics and Influence Stress Granule Formation

Multiple Sclerosis-Associated hnRNPA1 Mutations Alter hnRNPA1 Dynamics and Influence Stress Granule Formation

Altered Phase Separation and Cellular Impact in C9orf72-Linked ALS/FTD

Coordinating nucleoporin condensation and nuclear pore complex assembly

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