Signal de localisation nucléaire

Un signal de localisation nucléaire (SLN) ou NLS (de l'anglais Nuclear localization sequence) est une petite séquence d'acides aminés (8 à 10 acides aminés) qui cible les protéines vers le noyau de la cellule. Les protéines portant un signal de localisation nucléaire sont reconnues par la protéine importine dans le cytosol et sont guidées vers les pores nucléaires. La séquence de 8 à 10 acides aminés varie d'une protéine nucléaire à l'autre, mais elle est toujours riche en acides aminés chargés positivement (soit les acides aminés basiques : arginine, lysine, histidine). Elle peut être bipartite (en 2 parties) et n'est pas clivée après son entrée dans le noyau. Elle est essentielle pour le transport dans le noyau. Catégorie:Biologie moléculaire Catégorie:Protéine

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Noyau (biologie)

En biologie cellulaire, le noyau est une structure cellulaire présente dans la majorité des cellules eucaryotes et chez tous les organismes eucaryotes, et contenant l'essentiel du matériel génétique

Pore nucléaire

Les pores nucléaires sont de grands complexes protéiques (poids moléculaire estimé à 125 000 kDa) traversant l'enveloppe nucléaire, qui est une double membrane entourant le noyau des cellules eucary

Archaea

Les archées () ou Archaea (du grec ancien , « originel, primitif »), anciennement appelés archéobactéries, sont des microorganismes unicellulaires procaryotes, c'est-à-dire des êtres vivants constit

Scalable Production of AAV Vectors in Orbitally Shaken HEK293 Cells

Daniel Roman Blessing, Nicole Déglon, Vivianne Padrun, Bernard Schneider, Gabriel Vachey, Florian Maria Wurm

Adeno-associated virus (AAV) vectors are currently among the most commonly applied for in vivo gene therapy approaches. The evaluation of vectors during clinical development requires the production of considerable amounts of highly pure and potent vectors. Here, we set up a scalable process for AAV production, using orbitally shaken bioreactors and a fully characterized suspension-adapted cell line, HEKExpress. We conducted a proof-of-concept production of AAV2/8 and AAV2/9 vectors using HEKExpress cells. Furthermore, we compared the production of AAV2/9 vectors using this suspension cell line to classical protocols based on adherent HEK293 cells to demonstrate bioequivalence in vitro and in vivo. Following upstream processing, we purified vectors via gradient centrifugation and immunoaffinity chromatography. The in vitro characterization revealed differences due to the purification method, as well as the transfection protocol and the corresponding HEK293 cell line. The purification method and cell line used also affected in vivo transduction efficiency after bilateral injection of AAV2/9 vectors expressing a GFP reporter fused with a nuclear localization signal (AAV2/9-CBA-nlsGFP) into the striatum of adult mice. These results show that AAV vectors deriving from suspension HEKExpress cells are bioequivalent and may exhibit higher potency than vectors produced with adherent HEK293 cells.

2019

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The novel Parkinson's disease linked mutation G51D attenuates in vitro aggregation and membrane binding of alpha-synuclein, and enhances its secretion and nuclear localization in cells

Nadine Aït Bouziad, Mohamed Bilal Fares, Ana Jovicic, Hilal Lashuel, Martial Mbefo Kamdem

A novel mutation in the alpha-Synuclein (alpha-Syn) gene "G51D" was recently identified in two familial cases exhibiting features of Parkinson's disease (PD) and multiple system atrophy (MSA). In this study, we explored the impact of this novel mutation on the aggregation, cellular and biophysical properties of alpha-Syn, in an attempt to unravel how this mutant contributes to PD/MSA. Our results show that the G51D mutation significantly attenuates alpha-Syn aggregation in vitro. Moreover, it disrupts local helix formation in the presence of SDS, decreases binding to lipid vesicles C-terminal to the site of mutation and severely inhibits helical folding in the presence of acidic vesicles. When expressed in yeast, alpha-Syn(G51D) behaves similarly to alpha-Syn(A30P), as both exhibit impaired membrane association, form few inclusions and are non-toxic. In contrast, enhanced secreted and nuclear levels of the G51D mutant were observed in mammalian cells, as well as in primary neurons, where alpha-Syn(G51D) was enriched in the nuclear compartment, was hyper-phosphorylated at S129 and exacerbated alpha-Syn-induced mitochondrial fragmentation. Finally, post-mortem human brain tissues of alpha-Syn(G51D) cases were examined, and revealed only partial colocalization with nuclear membrane markers, probably due to post-mortem tissue delay and fixation. These findings suggest that the PD-linked mutations may cause neurodegeneration via different mechanisms, some of which may be independent of alpha-Syn aggregation.

Oxford University Press2014

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BCL9 is an essential component of canonical Wnt signaling that mediates the differentiation of myogenic progenitors during muscle regeneration

Michel Aguet

Muscle stem cells and their progeny play a fundamental role in the regeneration of adult skeletal muscle. We have previously shown that activation of the canonical Wnt/beta-catenin signaling pathway in adult myogenic progenitors is required for their transition from rapidly dividing transient amplifying cells to more differentiated progenitors. Whereas Wnt signaling in Drosophila is dependent on the presence of the co-regulator Legless, previous studies of the mammalian ortholog of Legless, BCL9 (and its homolog, BCL9-2), have not revealed an essential role of these proteins in Wnt signaling in specific tissues during development. Using Cre-lox technology to delete BCL9 and BCL9-2 in the myogenic lineage in vivo and RNAi technology to knockdown the protein levels in vitro, we show that BCL9 is required for activation of the Wnt/beta-catenin cascade in adult mammalian myogenic progenitors. We observed that the nuclear localization of beta-catenin and downstream TCF/LEF-mediated transcription, which are normally observed in myogenic progenitors upon addition of exogenous Wnt and during muscle regeneration, were abrogated when BCL9/9-2 levels were reduced. Furthermore, reductions of BCL9/9-2 inhibited the promotion of myogenic differentiation by Wnt and the normal regenerative response of skeletal muscle. These results suggest a critical role of BCL9/9-2 in the Wnt-mediated regulation of adult, as opposed to embryonic, myogenic progenitors.

Elsevier2009

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BIO-471: Cancer biology I

The course covers in detail molecular mechanisms of cancer development with emphasis on cell cycle control, genome stability, oncogenes and tumor suppressor genes.

CH-411: Cellular signalling

Presentation of selected signalling pathways with emphasis on both the mechanism of action of the molecules involved, molecular interactions and the role of their spatio-temporal organization within the cell, considering cellular dimensions and conditions.

BIO-212: Biological chemistry I

Biochemistry is a key discipline for the Life Sciences. Biological Chemistry I and II are two tightly interconnected courses that aim to describe and understand in molecular terms the processes that make life possible.