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Exploration below the tip of the microtubule

Periodic Reporting for period 3 - ICEBERG (Exploration below the tip of the microtubule)

Reporting period: 2021-10-01 to 2023-03-31

• What is the problem/issue being addressed?
The project is dedicated to microtubules. They are dynamic filaments that serve as tracks for the transport of proteins in cells. Cells contains about a hundreds of microtubules, which form a complex array. The architecture of the array, by determining the main directions for protein transport, is key to the main cell functions such as the adsorption and secretion of biochemical signals and nutrients. Cells adapt these functions to their environment via the rearrangement of the microtubule array, which takes advantage of the dynamic nature of microtubules that permanently grow and shrink stochastically.
In this project we put forward the hypothesis that microtubule dynamics is not restricted to this alternance of growing and shrinking and that they can loose and gain monomers all along their length, and by doing so they can modulate the composition of proteins binding along them. This novel view of microtubule biochemistry, happening not only at the tip of the microtubule but all along its shaft, open the possibility that they are not only dynamic tracks for protein transport but also antennas probing signals throughout the intracellular space.

• Why is it important for society?
Microtubules are present in all our cells and they are involved in most cell functions. As such they are the target of several therapies, including chemotherapy against cancer. A better understanding of microtubules would help us to improve current medical protocols and design novel strategies.
In parallel, from a material point of view, microtubules are quite unique. It is the only polymer that can grow and shrink in a presence of a given concentration of monomers. The regulation of their instability is mysterious. But it can also be seen as a tremendous advantage in the design of a novel class of biomaterials, the architecture, shape and mechanical properties of which would be sensitive and evolutive.

• What are the overall objectives?
For these reasons our project aims at understanding the mystery of microtubule dynamics. In particular, and in constrast with many other projects dedicated to microtubules we are not focusing on their instability but interested in their stability. We plan to test whether the molecular dynamics actually occur along the shaft of microtubules and in which conditions. Then we will investigate the properties that this new process may confer to microtubules. If microtubules are antennas, what do they sense ? Would this be a new way to talk to cells ?
1- We have shown that tubulin monomers can be exchanged along the shaft of microtubules, and not only at the end as previously thought. We have identified several mechanism regulating these exchanges : the presence of structural defects in the lattice of microtubules, the application of mechanical forces bending microtubules or the impact of molecular motors as they walk along microtubules when transporting cargoes full of proteins.

2- We found that microtubules have an intimate cross-talk with actin filaments which are responsible for the regulation of cell shape and the production of mechanical forces.

3- We also also shown that the stabilization of microtubules is involved in the polarisation of several cells types, and participate to their differentiation.
-> 1, we would like to identify the proteins that accompany the lattice turnover in order to understand the cellular signals that are sensed, by being captured or released, by this new biochemical process.

-> 2, we would like to know whether the interplay between actin network and microtubules modulate the dynamics of microtubule lattice. The actin network is the interface between intra-cellular cytoplasm and extra-cellular space. A crosstalk between actin network and microtubule would be a way for the microtubule network to receive and integrate informations form cell microenvironment. Like the discussion between our muscles and our nervous system.

-> 3, so far the dynamics of microtubule lattice has been observed in vitro, on isolated microtubules. We would like to test whether it also happen in living cells. And if it is case, then identify the key cellular events in which this novel process is involved.
this image illustrates that biochemical reactions may not be limited to the tip of microtubules