Project description
Molecular insight into the assembly of cell surface cilia
Cilia are tiny projections on the surface of specific cells such as airway epithelia which assist in movement, sensing and signalling. Dysfunction of cilia causes a heterogeneous group of diseases known as ciliopathies. The EU-funded CiliaTubulinCode project is interested to understand how cilia form from microtubules that constitute a conserved part of the cell’s cytoskeleton. The work focuses on the post-translational modifications and isotypes of tubulin, the protein component of microtubules. Researchers are investigating the hypothesis that this ‘tubulin code,’ as it is known, drives cilia assembly, affecting their properties and function.
Objective
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.
Fields of science
Keywords
Programme(s)
Funding Scheme
ERC-COG - Consolidator GrantHost institution
20157 Milano
Italy