Auxiliary barrier function of karyopherins at the Nuclear Pore Complex

Nuclear pore complexes (NPCs) are highly selective gateways that mediate nucleocytoplasmic transport (NCT) in eukaryotic cells. Recent discoveries have shown that leaky NPCs and defective NCT are linked to aging, neurodegenerative disorders, and viral pathogenesis. Nevertheless, their exact underlying cause(s) are unknown, reflecting an incomplete understanding of the key regulatory aspects of NPC function. At the heart of this problem lies the NPC permeability barrier, whose behavior has been largely modeled after the in vitro behavior of intrinsically disordered proteins termed phenylalanine-glycine nucleoporins (FG Nups). Nonetheless, this view is puzzling since certain key soluble nuclear transport receptors called β-karyopherins (Kapβs) are strongly enriched within NPCs in vivo. The experimental results reported in this thesis show that two major Kapβs, Kapβ1 (importinβ) and CRM1 (exportin1) are essential for fortifying the NPC permeability barrier against defective NCT and nuclear leakage in vivo. A further surprise is that CRM1 partially compensates for Kapβ1 upon depletion of the latter from the NPC, which suggests that Kapβ1 and CRM1 engage in a balancing act to reinforce NPC barrier function. Combining ex vivo and biophysical experimentation, as well as computational modeling, we further show how the occupancy of different Kapβs at the NPC is constrained by their size, cellular abundance, binding avidity to the FG Nups, and competition with other Kapβs, such as demonstrated for another Kapβ, Importin-5 (Imp5). Taken together, these findings provide important intersection points and raise new questions with respect to the causes of NPC leakage and defective NCT in aging and cellular pathologies

Les diaboliques du Perlesvaus ou les fantasmes de castration

The article investigates two mysterious feminine figures appearing in the 13th century Old French prose romance Le Haut Livre du Graal (Perlesvaus). Their ontological status, which remains uncertain until the end, gives them, along with the sexual violence and castration phantasms they incarnate, a highly troubling and uncanny aspect. The analysis highlights also the textual strategies used by the author in order to create such an effec

The "She-devils" in the "Perlesvaus" and the phantasms of castration

The article investigates two mysterious feminine figures appearing in the 13th century Old French prose romance Le Haut Livre du Graal (Perlesvaus). Their ontological status, which remains uncertain until the end, gives them, along with the sexual violence and castration phantasms they incarnate, a highly troubling and uncanny aspect. The analysis highlights also the textual strategies used by the author in order to create such an effect

“‘Chascun qui entre est entaiez’. Contempt in Béroul’s Tristan”

The article analyses the place of contempt in Béroul’s Romance of Tristan. Since its appearance in literature, the love of Tristan and Isolde has been the object of a double perception: on the one hand, a valued image of the “martyrdom of love”, and on the other hand, the much less positive image of a degrading, even despicable passion. It is interesting to note that contempt does not only appear in polemical works, but is, on the contrary, already present in the source text, especially in Béroul’s version. An in-depth study of the terms used to describe passion (including those used by the protagonists themselves), an analysis of the play of masks and of the episodes that stage the particularly humiliating situations in which all the characters without exception find themselves, reveals an ironic and sarcastic look by the author, and highlights the sometimes brutal, even cynical tone of the work. The analysis focuses on the major episodes of the story: the scene of the “clandestine rendezvous”, Tristan’s disguise as a leper and Isolde’s “ambiguous oath” (the crossing of the marsh).L’article analyse la place du mépris dans Le Roman de Tristan de Béroul. Dès son apparition dans la littérature, l’amour de Tristan et d’Iseut est l’objet d’une double perception : image valorisée du « martyre d’amour » d’une part, et d’autre part celle, nettement moins positive, d’une passion dégradante, voire méprisable. Il est intéressant de constater que le mépris n’apparaît pas seulement dans les œuvres polémiques, mais qu’il est au contraire bien présent déjà dans le texte-source, surtout dans la version de Béroul. Une étude approfondie des termes utilisés pour qualifier la passion (y compris ceux qu’emploient les protagonistes eux-mêmes), l’analyse du jeu de masques et des épisodes qui mettent en scène les situations particulièrement humiliantes, dans lesquelles se retrouvent tous les personnages sans exception, révèle un regard ironique et narquois de l’auteur, et met en valeur une tonalité parfois brutale, voire cynique, de l’œuvre. L’analyse s’organise autour des grands épisodes du récit : le « rendez-vous épié », le déguisement de Tristan en lépreux et le « serment ambigu » d’Iseut (le passage du marais)

"The ugly truth" : Cahus’ dream revisited

The aim of this paper is to propose an analysis of the Cahus’ Dream, a well known episode of the Perlesvaus, Arthurian romance from the 13th century, within the context of the medieval dream theories. Inspired mostly by Macrobius’ Commentary on the Dream of Scipio – fo cusing on the divinatory (or deceptive/ illusory) role of dreams – as well as by Tertullian’s and Augustine’s Christian refl ections on the relations between the soul and the sleeping body, these theories permit to shed a new light on the oneiric adventure of the squire. In fact, the author furnishes numerous clues which make it look as an insomnium or fantasma: a false, illusory dream, deprived of any deeper signifi cation. Thus, unable of uncovering some hidden, symbolic meaning, the mirage paradoxically turns out to be a material, "ugly", as the text has it, truth, blurring the border between dream and reality in a most confusing way, and setting the specific Perlesvaus tone from the very beginning of the romance

Spleen and ideal : the concept of the "fin’amor" in Thomas’ "Tristan"

Spleen and ideal. The concept of the fin’amor in Thomas’ Tristan The concept of fin’amor in Thomas’ Tristan is traditionally subject to two interpretations: either it is glorified as a religion, with lovers as its martyrs, or it is criticized within the framework of Christian principles. This paper proposes an alternative to such interpretative dichotomy: it attempts to prove that glorifying the fin’amor as an ideal does not mean idealizing the lovers. In fact, Thomas judges severely his characters not in the name of Christian religion but in the name of an entirely profane, yet highly spiritual ideal of courtly love. The lovers, although far from being its embodiment, still aspire and refer to it, suffering from their own imperfection. This tension is highlighted by the aesthetics of doubling characterizing Thomas’ writing

La peur du diable dans Vie des peres (XIIIe siècle)

The article analyses the vision of the devil in the selected tales of the Vie des peres, a collection of pious tales from the thirteenth century, freely inspired by patristic literature and medieval exempla. The period in which the collection was written, the thirteenth century, bridges the gap between the early and late Middle Ages: it is a time when the perception of the devil is changing, and he is becoming increasingly feared. The analysis focuses mainly on four stories in which the devil is at the centre of the story, and in which his very image is a source of fear and a key element of the story: ‘Devil’s Mouth’, ‘Devils Vision’ and two versions of ‘Devil’s Image’. The vision of the devil in these stories coincides with the teratological vision that is dominant in the iconography, to which the stories directly allude. The message of these stories is generally positive: the protagonists almost always manage to overcome their fears and free themselves from the power of the devil. In this way, the authors avoid the trap of Manichaeism: the devil, despite his cunning and sophistication, is in the end only a caricature of an angel, unable to oppose God effectively. The fear of the devil appears several times on the pages of Vie des peres, but it is the message of hope that dominates.L’article analyse la vision du diable dans les contes choisis de la Vie des peres, recueil de contes pieux du XIIIe siècle, librement inspiré de la littérature patristique et des exempla médiévaux. La période de la rédaction du recueil, le treizième siècle, marque la transition entre le haut et le bas Moyen Âge : c’est une époque où la perception du diable évolue et où celui-ci devient de plus en plus redouté. L’analyse se focalise surtout sur quatre récits dans lesquels le diable est au centre de l’histoire, et où son image même est source de peur et élément clé du récit : « Gueule du diable », « Vision de diables » et deux versions d’« Image du diable ». La vision du diable dans ces histoires coïncide avec la vision tératologique qui domine dans l’iconographie, à laquelle les histoires citées font d’ailleurs directement allusion. Le message de ces histoires est généralement positif : les protagonistes parviennent presque toujours à surmonter leurs peurs et à se libérer du pouvoir du diable. Les auteurs évitent ainsi le piège du manichéisme : le diable, malgré sa ruse et sa sophistication, n’est finalement qu’une caricature d’ange, incapable de s’opposer efficacement à Dieu. La peur du diable apparaît à plusieurs reprises sur les pages de la Vie des peres, mais c’est le message d’espoir qui domine

Karyopherin enrichment and compensation fortifies the nuclear pore complex against nucleocytoplasmic leakage

Nuclear pore complexes (NPCs) discriminate nonspecific macromolecules from importin and exportin receptors, collectively termed "karyopherins" (Kaps), that mediate nucleocytoplasmic transport. This selective barrier function is attributed to the behavior of intrinsically disordered phenylalanine-glycine nucleoporins (FG Nups) that guard the NPC channel. However, NPCs in vivo are typically enriched with different Kaps, and how they impact the NPC barrier remains unknown. Here, we show that two major Kaps, importinβ1/karyopherinβ1 (Kapβ1) and exportin 1/chromosomal maintenance 1 (CRM1), are required to fortify NPC barrier function in vivo. Their enrichment at the NPC is sustained by promiscuous binding interactions with the FG Nups, which enable CRM1 to compensate for the loss of Kapβ1 as a means to maintain NPC barrier function. However, such a compensatory mechanism is constrained by the cellular abundances and different binding kinetics for each respective Kap, as evidenced for importin-5. Consequently, we find that NPC malfunction and nucleocytoplasmic leakage result from poor Kap enrichment