ENDOMYOSHAPE

Identification of the molecular mechanisms whereby actin and myosin1b shape sorting endosomes

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 Obiettivo del progetto (Objective)

'Sorting events that occur in endosomes are very important for cellular trafficking of proteins and membranes along the endocytic pathway. The shape of sorting endosomes plays a major role in their function. However, the molecular mechanisms that control the shape of sorting endosomes are far from being elucidated. Motors and cytoskeleton can influence the shape of membranes, especially of high curvature, by establishing tension on membranes. I propose to study the role of an actin cytoskeleton-motor, myosin 1b (Myo1b), a mammalian class I myosin, in regulating the morphology of sorting endosomes. Myo1b localizes to sorting endosomes and when overexpressed increases the formation of tubules in endosomes. I hypothesize that Myo1b induces the formation of membrane tubules by recruiting actin filaments that generates a pulling force on endosomal membranes. The aim of my project is to understand the molecular mechanisms involved in tubule formation mediated by Myo1b in sorting endosomes in mammalian cells. First, I will identify the mechanism by which Myo1b localizes to sorting endosomes. Second, I will establish whether Myo1b recruits actin filaments to sorting endosomes. Third, I will show that Myo1b is required for the formation of tubules in membranes of sorting endosomes. Fourth, I will investigate which sorting events on endosomes are dependent on Myo1b function. These aims employ molecular biology, biochemistry, cell biology and biophysics methodologies in a novel approach to study the shape of sorting endosomes. Ultimately, I wish to unravel the molecular mechanism whereby the Myo1b-dependent recruitment of actin to endosomes regulates endosomal morphology and endocytic trafficking.'

Introduzione (Teaser)

Transporting materials in and out of a cell is a complex process and requires the reshaping of membranes to form endosomes, transport vesicles. The role of two proteins in membrane remodelling has come under the European research microscope.

Descrizione progetto (Article)

The cell is a dynamic environment that needs to import and export molecules. Transporting materials to the inside requires a way round the fact that the cell membrane is impermeable to large polar molecules such as proteins. Accomplishing this task for the cell, the process of endocytosis involves the remodelling of the restricting membrane.

together with actin which forms a cytoskeleton, myosin plays a part in membrane reshaping and deformation to form vesicles. At the plasma membrane, for example, invagination forms endosomes. However, the role of myosin 1 and actin in remodelling intracellular membrane systems such as the trans-Golgi network (TGN) have so far remained unknown.

the EU-funded project 'Identification of the molecular mechanisms whereby actin and myosin1b shape sorting endosomes' (Endomyoshape) aimed to dig into the molecular mechanics of endosome formation at the TGN. The scientists focused on the role of a myosin 1 protein, Myo1b, in the regulation of endocytosis.

endomyoshape found a pool of Myo1b at the TGN and demonstrated that this particular myosin, together with the actin cytoskeleton, promotes the formation of tubular carrier precursors arising from the TGN. Myosin1b generates a force that controls the assembly of F-actin foci and, together with the actin cytoskeleton, promotes the formation of tubules.

the project has therefore provided evidence that actin and myosin1b regulate organelle shape and initiate post-Golgi carrier formation by regulating actin assembly and remodelling of TGN membranes.

uncovering the regulation of endocytic trafficking promises to be the key to many diseases. Some bleeding and pigmentation disorders, forms of neuropathy, kidney disease and blindness are part of this huge array. A number of cancers are also associated with defective modulation of the endocytic pathway.