Spatial control of nucleoporin condensation by fragile X‐related proteins

Agote-Arán, Arantxa; Schmucker, Stéphane; Jeřábková, Kateřina; Boyer, Inès Jmel; Berto, Alessandro; Pacini, Laura; Ronchi, Paolo; Kleiss, Charlotte; Guérard, Laurent; Schwab, Yannick; Moine, Hervé; Mandel, Jean‐Louis; Jacquemont, Sébastien; Bagni, Claudia; Sumara, Izabela

doi:10.15252/embj.2020104467

Cited by 28 publications

(44 citation statements)

References 67 publications

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“…We also observed cytoplasmic inclusions of nuclear pore components, as well as of RanGAP1,a key protein regulating nucleocytoplasmic shuttling function, which recapitulates previous observations in ALS patients 15,21 . These cytoplasmic nuclear pore inclusions were analogous to the inclusions recently observed upon FXR1 downregulation 74 . Hence, further research is needed to determine their origin and their potential relevance to ALS, especially as these cytoplasmic nucleoporin inclusions co-occur with p62 inclusions also found in ALS patients, in particular C9ORF72 HRE patients [75][76][77] .…”

Section: Discussionsupporting

confidence: 80%

Loss of nucleoporin Nup50 is a risk factor for amyotrophic lateral sclerosis

Megat

Mora

Sanogo

et al. 2021

Preprint

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The genetic basis of amyotrophic lateral sclerosis (ALS) is still incompletely understood. Using two independent genetic strategies, we show here that a large part of ALS heritability lies in genes expressed in inhibitory and excitatory neurons, especially at splicing sites regulated by a defined set of RNA binding proteins including TDP-43 and FUS. We conducted a transcriptome wide association study (TWAS) and identified 59 loci associated with ALS, including 14 previously identified genes, some of them not previously reaching significance in genome wide association studies. Among the 45 novel genes, several genes are involved in pathways known to be affected in ALS such as mitochondrial metabolism (including ATP5H, ATP5D, BCS1L), proteostasis (including COPS7A, G2E3, TMEM175, USP35) or gene expression and RNA metabolism (including ARID1B, ATXN3, PTBP2, TAF10). Interestingly, decreased expression of NUP50, a constrained gene encoding a nuclear pore basket protein, was associated with ALS in TWAS (Zscore = -4, FDR = 0.034). 11 potentially pathogenic variants (CADD score > 20) in 23 patients were identified in the NUP50 gene, most of them in the region of the protein mediating interaction with Importin alpha, and including 2 frameshift mutations. In cells from two patients carrying NUP50 variants, we showed decreased levels of NUP50 protein. Importantly, knocking down Nup50 led to increased neuronal death associated with p62 and nucleoporin inclusions in cultured neurons, and motor defects in Drosophila and zebrafish models. In all, our study identifies alterations in splicing in neurons as a critical pathogenic process in ALS, uncovers several new loci potentially contributing to ALS missing heritability, and provides genetic evidence linking nuclear pore defects to ALS.

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Section: Discussionsupporting

confidence: 80%

Loss of nucleoporin Nup50 is a risk factor for amyotrophic lateral sclerosis

Megat

Mora

Sanogo

et al. 2021

Preprint

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“…Membrane-free cytoplasmic Nups are also described as largely soluble [ 84 ] or as condensates in stress granules during a variety of insults [ 85 ]. Very recently, an additional form of cytoplasmic Nup congregation with liquid–liquid interaction properties was found in the absence of the fragile X-related protein [ 86 ]. Yet, none of these structures are reminiscent of, and probably do not relate to, LD.…”

Section: Discussionmentioning

confidence: 99%

Lipid Droplets Are a Physiological Nucleoporin Reservoir

Kumanski

Viart

Kossida

et al. 2021

Cells

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Lipid Droplets (LD) are dynamic organelles that originate in the Endoplasmic Reticulum and mostly bud off toward the cytoplasm, where they store neutral lipids for energy and protection purposes. LD also have diverse proteins on their surface, many of which are necessary for the their correct homeostasis. However, these organelles also act as reservoirs of proteins that can be made available elsewhere in the cell. In this sense, they act as sinks that titrate key regulators of many cellular processes. Among the specialized factors that reside on cytoplasmic LD are proteins destined for functions in the nucleus, but little is known about them and their impact on nuclear processes. By screening for nuclear proteins in publicly available LD proteomes, we found that they contain a subset of nucleoporins from the Nuclear Pore Complex (NPC). Exploring this, we demonstrate that LD act as a physiological reservoir, for nucleoporins, that impacts the conformation of NPCs and hence their function in nucleo-cytoplasmic transport, chromatin configuration, and genome stability. Furthermore, our in silico modeling predicts a role for LD-released fatty acids in regulating the transit of nucleoporins from LD through the cytoplasm and to nuclear pores.

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“…Different types of fragile X‐granules are expressed in neurons, where they regulate transport, localization, stability, and translation of target RNAs. In the current study, Agote‐Aran et al () expand our view on FXR proteins and show that they also control the assembly of granules containing nucleoporins, the building blocks of nuclear pore complexes (NPCs).…”

Section: Fxr1 Participates To Npc Homeostasismentioning

confidence: 57%