Description du projet
Des informations moléculaires sur l’assemblage des cils cellulaires
Les cils sont de minuscules projections situées à la surface de cellules spécifiques comme l’épithélium des voies respiratoires qui contribuent au mouvement, à la détection et à la signalisation. Le dysfonctionnement des cils entraîne un groupe hétérogène de maladies connues sous le terme de ciliopathies. Le projet CiliaTubulinCode, financé par l’UE, cherche à comprendre comment les cils se forment à partir des microtubules qui proviennent d’une partie intacte du cytosquelette de la cellule. Les travaux se concentreront sur les modifications post-traductionnelles et les isotypes de la tubuline, la protéine structurale des microtubules. Les chercheurs examinent l’hypothèse selon laquelle ce «code tubuline», comme il est connu, contribue à l’assemblage des cils, affectant leurs propriétés et leur fonction.
Objectif
This project aims at understanding of the role of the tubulin code for self-organization of complex microtubule based structures. Cilia turn out to be the ideal structures for the proposed research.
A cilium is a sophisticated cellular machine that self-organizes from many protein complexes. It plays motility, sensory, and signaling roles in most eukaryotic cells, and its malfunction causes pathologies. The assembly of the cilium requires intraflagellar transport (IFT), a specialized bidirectional motility process that is mediated by adaptor proteins and direction specific molecular motors. Work from my lab shows that anterograde and retrograde IFT make exclusive use of the B-tubules and A-tubules, respectively. This insight answered a long standing question and shows that functional differentiation of tubules exists and is important for IFT.
Tubulin post-translational modifications (PTMs) contribute to a tubulin code, making microtubules suitable for specific functions. Mutation of tubulin-PTM enzymes can have dramatic effects on cilia function and assembly. However, we do not understand of the role of tubulin-PTMs in cilia. Therefore, I propose to address the hypotheses that the tubulin code contributes to regulating bidirectional IFT motility, and more generally, that the tubulin code is a key player in structuring complex cellular assembly processes in space and time.
This proposal aims at (i) understanding if tubulin-PTMs are necessary and/or sufficient to regulate the bidirectionality of IFT (ii) examining how the tubulin code regulates the assembly of cilia and (iii) generating a high-resolution atlas of tubulin-PTMs and their respective enzymes.
We will combine advanced techniques encompassing state-of-the-art cryo-electron tomography, biochemical imaging, fluorescent microscopy, and in vitro assays to achieve molecular and structural understanding of the role of the tubulin code in the self-organization of cilia and of microtubule based cellular structures.
Champ scientifique
Mots‑clés
Programme(s)
Régime de financement
ERC-COG - Consolidator GrantInstitution d’accueil
20157 Milano
Italie