Control of nuclear organization by F-actin binding proteins

Abstract

The regulation of nuclear shape and deformability is a key factor in controlling diverse events from embryonic development to cancer cell metastasis, but the mechanisms governing this process are still unclear. Our recent study demonstrated an unexpected role for the F-actin bundling protein fascin in controlling nuclear plasticity through a direct interaction with Nesprin-2. Nesprin-2 is a component of the LINC complex that is known to couple the F-actin cytoskeleton to the nuclear envelope. We demonstrated that fascin, which is predominantly associated with peripheral F-actin rich filopodia, binds directly to Nesprin-2 at the nuclear envelope in a range of cell types. Depleting fascin or specifically blocking the fascin-Nesprin-2 complex leads to defects in nuclear polarization, movement and cell invasion. These studies reveal a novel role for an F-actin bundling protein in control of nuclear plasticity and underline the importance of defining nuclear-associated roles for F-actin binding proteins in future.

Keywords: Fascin; Nesprin-2; actin; cell migration; nuclear deformation; nuclear movement.

Figure 1.

Fascin function at the cell periphery and NE/nucleus. (A) Migrating cells use finger-like protrusions called filopodia to explore the microenvironment. (B) Schematic view of a simplified filopodium where fascin, which is highly upregulated in tumor cells and cancer metastasis, is critical for F-actin bundling and filopodia stability. Fascin bundles F-actin by binding 2 adjacent filaments and thereby stabilizes filopodia. (C) Interaction of filopodia with the ECM can induce twisting and bending that exerts forces on actin filaments, potentially altering fascin phosphorylation status and thus F-actin bundling. (D) Forces and/or secreted factors can induce translocation of fascin to the nuclear periphery where it interacts with Nes2G, which is anchored at the outer NE via the KASH domain and interacts with SUN at the inner NE. Nes2G can directly interact with F-actin via its CH domain. Fascin stabilizes this interaction and thereby can efficiently regulate nuclear positioning and deformation during cell migration. Only the giant isoform of Nesprin-2 is shown in this simplified diagram. Fascin can also be shuttled into the nucleus and contributes to intra-nuclear actin filament bundling. CH, calponin homology; ECM, extracellular matrix; F-actin, filamentous actin; G-actin, globular actin; KASH, Klarsicht, ANC-1 and Syne homology; NE, nuclear envelope; Nes2G, Nesprin-2 Giant; P, phosphorylation; S39, Serine 39; SUN, Sad1p, UNC-84.