Publications by authors named "Katerina Jerabkova"

5 Publications

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Deubiquitylase UCHL3 regulates bi-orientation and segregation of chromosomes during mitosis.

FASEB J 2020 09 1;34(9):12751-12767. Epub 2020 Aug 1.

Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Department of development and stem cells, Illkirch, France.

Equal segregation of chromosomes during mitosis ensures euploidy of daughter cells. Defects in this process may result in an imbalance in the chromosomal composition and cellular transformation. Proteolytic and non-proteolytic ubiquitylation pathways ensure directionality and fidelity of mitotic progression but specific mitotic functions of deubiquitylating enzymes (DUBs) remain less studied. Here we describe the role of the DUB ubiquitin carboxyl-terminal hydrolase isozyme L3 (UCHL3) in the regulation of chromosome bi-orientation and segregation during mitosis. Downregulation or inhibition of UCHL3 leads to chromosome alignment defects during metaphase. Frequent segregation errors during anaphase are also observed upon inactivation of UCHL3. Mechanistically, UCHL3 interacts with and deubiquitylates Aurora B, the catalytic subunit of chromosome passenger complex (CPC), known to be critically involved in the regulation of chromosome alignment and segregation. UCHL3 does not regulate protein levels of Aurora B or the binding of Aurora B to other CPC subunits. Instead, UCHL3 promotes localization of Aurora B to kinetochores, suggesting its role in the error correction mechanism monitoring bi-orientation of chromosomes during metaphase. Thus, UCHL3 contributes to the regulation of faithful genome segregation and maintenance of euploidy in human cells.
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http://dx.doi.org/10.1096/fj.202000769RDOI Listing
September 2020

Spatial control of nucleoporin condensation by fragile X-related proteins.

EMBO J 2020 10 24;39(20):e104467. Epub 2020 Jul 24.

Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France.

Nucleoporins (Nups) build highly organized nuclear pore complexes (NPCs) at the nuclear envelope (NE). Several Nups assemble into a sieve-like hydrogel within the central channel of the NPCs. In the cytoplasm, the soluble Nups exist, but how their assembly is restricted to the NE is currently unknown. Here, we show that fragile X-related protein 1 (FXR1) can interact with several Nups and facilitate their localization to the NE during interphase through a microtubule-dependent mechanism. Downregulation of FXR1 or closely related orthologs FXR2 and fragile X mental retardation protein (FMRP) leads to the accumulation of cytoplasmic Nup condensates. Likewise, models of fragile X syndrome (FXS), characterized by a loss of FMRP, accumulate Nup granules. The Nup granule-containing cells show defects in protein export, nuclear morphology and cell cycle progression. Our results reveal an unexpected role for the FXR protein family in the spatial regulation of nucleoporin condensation.
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http://dx.doi.org/10.15252/embj.2020104467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560220PMC
October 2020

Intraflagellar Transport Complex B Proteins Regulate the Hippo Effector Yap1 during Cardiogenesis.

Cell Rep 2020 07;32(3):107932

Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France; Université de Strasbourg, Illkirch, France; Sorbonne Université, Collège Doctoral, F-75005, Paris, France; Department of Bioengineering, Imperial College London, London, UK. Electronic address:

Cilia and the intraflagellar transport (IFT) proteins involved in ciliogenesis are associated with congenital heart diseases (CHDs). However, the molecular links between cilia, IFT proteins, and cardiogenesis are yet to be established. Using a combination of biochemistry, genetics, and live-imaging methods, we show that IFT complex B proteins (Ift88, Ift54, and Ift20) modulate the Hippo pathway effector YAP1 in zebrafish and mouse. We demonstrate that this interaction is key to restrict the formation of the proepicardium and the myocardium. In cellulo experiments suggest that IFT88 and IFT20 interact with YAP1 in the cytoplasm and functionally modulate its activity, identifying a molecular link between cilia-related proteins and the Hippo pathway. Taken together, our results highlight a noncanonical role for IFT complex B proteins during cardiogenesis and shed light on a mechanism of action for ciliary proteins in YAP1 regulation.
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http://dx.doi.org/10.1016/j.celrep.2020.107932DOI Listing
July 2020

CRMP2 mediates Sema3F-dependent axon pruning and dendritic spine remodeling.

EMBO Rep 2020 03 9;21(3):e48512. Epub 2020 Jan 9.

Department of Molecular Neurobiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.

Regulation of axon guidance and pruning of inappropriate synapses by class 3 semaphorins are key to the development of neural circuits. Collapsin response mediator protein 2 (CRMP2) has been shown to regulate axon guidance by mediating semaphorin 3A (Sema3A) signaling; however, nothing is known about its role in synapse pruning. Here, using newly generated crmp2 mice we demonstrate that CRMP2 has a moderate effect on Sema3A-dependent axon guidance in vivo, and its deficiency leads to a mild defect in axon guidance in peripheral nerves and the corpus callosum. Surprisingly, crmp2 mice display prominent defects in stereotyped axon pruning in hippocampus and visual cortex and altered dendritic spine remodeling, which is consistent with impaired Sema3F signaling and with models of autism spectrum disorder (ASD). We demonstrate that CRMP2 mediates Sema3F signaling in primary neurons and that crmp2 mice display ASD-related social behavior changes in the early postnatal period as well as in adults. Together, we demonstrate that CRMP2 mediates Sema3F-dependent synapse pruning and its dysfunction shares histological and behavioral features of ASD.
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http://dx.doi.org/10.15252/embr.201948512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054682PMC
March 2020

Cullin 3, a cellular scripter of the non-proteolytic ubiquitin code.

Semin Cell Dev Biol 2019 09 28;93:100-110. Epub 2018 Dec 28.

Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France; Centre National de la Recherche Scientifique UMR 7104, Strasbourg, France; Institut National de la Santé et de la Recherche Médicale U964, Strasbourg, France; Université de Strasbourg, Strasbourg, France. Electronic address:

Cullin-RING ubiquitin ligases (CRLs) represent the largest family of E3 ubiquitin ligases that control most if not all cellular processes. In CUL3-based CRLs, the substrate specificity is conferred by the interaction with one of around 183 existing BTB proteins, implying a broad spectrum of possible ubiquitylation signals and possible direct ubiquitylation substrates. Indeed, CUL3-based E3-ligases can catalyze various proteolytic and non-proteolytic ubiquitin signals regulating many physiological and pathophysiological states. Here, we discuss the recent studies focusing on the non-proteolytic CUL3-based signaling in mammalian cells, which emerge as important pathways during cell division, embryonic development as well as other biological processes. Mechanistically, non-proteolytic ubiquitin signals generated by CUL3 E3-ligases often regulate substrates' interactions with other downstream factors or their subcellular localization. Existing data also demonstrate an interplay with the proteolytic ubiquitylation catalyzed on the same substrates by different E3-ligases or by the same CUL3-BTB CRL3s on different substrates. In future, a deeper understanding of the upstream spatiotemporal regulatory mechanisms will help to dissect this fascinating CUL3 ubiquitin code.
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http://dx.doi.org/10.1016/j.semcdb.2018.12.007DOI Listing
September 2019
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