The filamin-B–refilin axis – spatiotemporal regulators of the actin-cytoskeleton in development and disease

Abstract

During development, cycles of spatiotemporal remodeling of higher-order networks of actin filaments contribute to control cell fate specification and differentiation. Programs for controlling these dynamics are hard-wired into actin-regulatory proteins. The filamin family of actin-binding proteins exert crucial mechanotransduction and signaling functions in tissue morphogenesis. Filamin-B (FLNB) is a key player in chondrocyte progenitor differentiation for endochondral ossification. Biallelic loss-of-function mutations or gain-of-function mutations in cause two groups of skeletal disorders that can be attributed to either the loss of repressive function on TGF-β signaling or a disruption in mechanosensory properties, respectively. In this Review, we highlight a unique family of vertebrate-specific short-lived filamin-binding proteins, the refilins (refilin-A and refilin-B), that modulate filamin-dependent actin crosslinking properties. Refilins are downstream TGF-β effectors in epithelial cells. Double knockout of both refilin-A and refilin-B in mice results in precocious ossification of some axial skeletal elements, leading to malformations that are similar to those seen in-deficient mice. Based on these findings, we present a model summarizing the role of refilins in regulating the mechanosensory functions of FLNB during skeletal development. We also discuss the possible contribution of refilins to FLNB-related skeletal pathologies that are associated with gain-of-function mutations.

Actin on and around the Nucleus

“…Cells that do not assemble perinuclear actin caps, such as cancer cells or cells lacking α-actinin-1, do not orient their nucleus in the direction of migration even if dorsal and transverse actin fibers are intact. At the nuclear periphery, the actin branching protein filamin A is converted into an actin bundler by RefilinB to organize the actin structures above the nucleus [36] and is also involved in mechanotransduction [37]. Interestingly, depletion of the Rac1-selective guanine exchange factor (GEF) Sif and Tiam1-like exchange factor (STEF), localized at the NE and colocalizing with Nesprin-2, leads to a decrease of perinuclear actin caps [38].…”

Exploration of Oxygen-Induced Retinopathy Model to Discover New Therapeutic Drug Targets in Retinopathies

“…Filamins act as actin binding scaffold proteins that maintain ECM connections. They act as mechanoresponsive actin crosslinkers and are important players in the actomyosin network and crucial for mechanotransduction (Baudier et al, 2018;Balassy et al, 2019). Thus, they modulate the interactions between actin cytoskeleton and the ECM, enabling changes in the transmission of forces at the cell periphery (Razinia et al, 2012).…”

FLN-1/Filamin is required to anchor the actomyosin cytoskeleton and for global organization of sub-cellular organelles in a contractile tissue

“…This may explain why the phenotypes we observed are more dramatic than the loss of filamin phenotypes seen in other systems. Various familial filaminopathies are associated with filamin A ,B, and C in humans, although the molecular mechanisms behind these disorders are not well understood (Baudier, Jenkins, & Robertson, 2018;Duff et al, 2011;Ferrer & Olivé, 2008;Kley et al, 2007;Razinia et al, 2012;Vorgerd et al, 2005;Wade, Halliday, Jenkins, O'Neill, & Robertson, 2020). Our work also suggests that in addition to the known roles of filamin as an actin crosslinker and signaling scaffold, loss of filamin in non-redundant systems can result in global rearrangement of the cell cytoskeleton and organelles.…”