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 The functional role of the endocytic protein syndapin in controlling actin cytoskeletal organization and dynamics. - DFG-Proritiy program SPP1150

(Roser Pinyol i Agelet, Anne Braun, Rashmi Ahuja)

The actin cytoskeleton is a complex and highly organized structure, yet it is dynamic and responds to a variety of inner and outer clues. It is well known that the plasma membrane of all mammalian cells is connected to a cortical cytoskeleton, which is crucial for mechanical stability but also for the establishment and rearrangement of defined cell morphological features. The actin cytoskeleton is also important for the attachment of cells to the extracellular matrix as well as to neighbouring cells and plays an indispensable role in cell division. Furthermore, spreading and movement of cells is critically dependent on the actin cytoskeleton; this also holds true for the movement of membrane-enclosed compartments within the cell. In addition to motor protein-dependent transport mechanisms, actin polymerization-propelled processes have been observed at small vesicular structures. Such actin-driven mechanisms are also exploited by a variety of intracellular pathogens for their intracellular motility and for infecting neighbouring cells. All the processes described rely on the polymerization of actin monomers to actin fibers as the driving force.

Actin polymerization, however, is not a kinetically favored process as long as not at least an actin trimer has been assembled. Cores for rapid filament formation can either be obtained by cutting or decapping existing filaments to generate more free ends or by assembling small nuclei of at least three actin monomers in the so-called nucleation reaction. The nucleation reaction is catalyzed by a protein complex, which includes actin-related proteins that can serve as seeds for rapid polymerization, the Arp2/3 complex. Since the polymerization of actin fibers from such small nuclei can proceed spontaneously, the activity of the Arp2/3 complex has to be tightly controlled.

Since actin and the Arp2/3 complex are basic, general components, a specific linkage of cytoskeletal functions to the huge variety of cellular processes actin is involved in will require tissue specificity but also temporal and spatial specificity within a given cell. Some of this specificity may be provided by the different Arp2/3 complex activators, the majority of which however belong to one protein family, the Wiskott-Aldrich syndrome protein (WASP) family. Thus, a further group of proteins interacting with Arp2/3 complex activator molecules seems required for the control and the linkage of this machinery to distinct cellular functions.

With syndapins, we have identified proteins that interact with the Arp2/3 complex activator N-WASP but are furthermore functional components of membrane trafficking processes, because they also associate with the large GTPase dynamin, which is crucial for vesicle formation processes at different donor membranes. Our present analyses, which were mainly performed with the syndapin I isoform, suggest that syndapins are capable to elicit local actin polymerization. In this project, we want to address whether this is a general feature of syndapin function and we will try to unravel the detailed molecular mechanisms underlying such an activity. A central focus will hereby be the involvement of Arp2/3 complex-activators of the WASP family. These analyses shall lead to a deeper understanding of motility based on actin polymerization forces. We will then focus on the ability of syndapin proteins to link actin dynamics to membranes and membrane trafficking processes. A detailed analysis of such a connection and its regulation shall help to unravel the complex interplay of membranes and the cortical cytoskeleton giving rise to and changing distinct cellular morphologies. These insights will promote our understanding of the abilities of cells to respond to inner and outer stimuli, which is indispensable for a plethora of functions in life.

Syndapins link endocytic vesicle formation and the actin cytoskeleton.

Fig. 1: Syndapins link endocytic vesicle formation and the actin cytoskeleton. Syndapins interact with both the GTPase dynamin that mediates vesicle formation processes at the plasma membrane and with the neuronal Wiskott-Aldrich-Syndrom protein (N-WASP), a potent stimulator of the prominent cellular actin polymerization machinery, as shown in vitro and in vivo. Interfering with dynamin functions by overexpression of the dynamin-binding module of syndapins (such cells appear in red) blocks receptor-mediated endocytosis that can be followed by a green fluorescent tracer (left microscopic image). Overexpression of syndapins as full-length proteins (in the cells marked by stars in the right microscopic image) elicits a striking reorganization of the cortical cytoskeleton, the induction of numerous actin-rich, thin protrusions from the surface of the cells. Adapted from Qualmann & Kelly (2000).

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