The mechanobiology of actin cytoskeletal proteins during cell–cell fusion

Abstract

Myosin II and spectrin β display mechanosensitive accumulations in invasive protrusions during cell–cell fusion of Drosophila myoblasts. The biochemical inhibition and deactivation of these proteins results in significant fusion defects. Yet, a quantitative understanding of how the protrusion geometry and fusion process are linked to these proteins is still lacking. Here we present a quantitative model to interpret the dependence of the protrusion size and the protrusive force on the mechanical properties and microstructures of the actin cytoskeleton and plasma membrane based on a mean-field theory. We build a quantitative linkage between mechanosensitive accumulation of myosin II and fusion pore formation at the tip of the invasive protrusion through local area dilation. The mechanical feedback loop between myosin II and local deformation suggests that myosin II accumulation possibly reduces the energy barrier and the critical radius of fusion pores. We also analyse the effect of spectrin β on maintaining the proper geometry of the protrusions required for the success of cell–cell fusion.

ARHGEF18/p114RhoGEF Coordinates PKA/CREB Signaling and Actomyosin Remodeling to Promote Trophoblast Cell-Cell Fusion During Placenta Morphogenesis

“…Increased mechanical tension and cytoskeletal remodeling are thought to be required for cell-cell fusion ( Kim et al, 2015 ; Cong et al, 2019 ). Therefore, we asked whether p114RhoGEF is required for forskolin-induced actomyosin remodeling.…”

“…Strikingly, p114RhoGEF was not only required for PKA-stimulated cell-cell fusion but also for the rapid induction of junctional foci of active myosin. Cytoskeletal remodeling and the thereby generated mechanical tension are thought to be key drivers of cell-cell fusion by promoting the close proximity of the neighboring plasma membranes required for fusion to occur ( Kim et al, 2015 ; Cong et al, 2019 ). In the placenta, tissue stiffness increases to levels that start to attenuate cell-cell fusion in preeclampsia, a disease caused by defective trophoblast differentiation, suggesting that increased tissue stiffness may prevent the close membrane approximation required for fusion ( Kilic et al, 2015 ; Ma et al, 2020 ).…”

“…Thus, p114RhoGEF and its downstream partner AKAP12 are required for efficient PKA/CREB pathway activation to induce cell-cell fusion as well as expression of PKA/CREB-dependent target genes required for syncytiotrophoblast differentiation. Increased mechanical tension and cytoskeletal remodeling are thought to be required for cell-cell fusion (Kim et al, 2015;Cong et al, 2019). Therefore, we asked whether p114RhoGEF is required for forskolin-induced actomyosin remodeling.…”

Actin crosslinking by α-actinin averts viscous dissipation of myosin force transmission in stress fibers

“…In the region surrounding the fusion pore, F-actin, myosin II, and α-actinin are accumulated. 88 , 89 While actomyosin contraction in this region expands the fusion pore to complete cell-cell fusion, 90 , 91 α-actinin may promote this process by ensuring force transmission from the actomyosin complex to the fusion pore. Furthermore, when muscle is regenerated after injury, the myogenic progenitor cells, satellite cells, migrate to the damaged site in muscle for restoration, 92 where α-actinin may be involved in the regulation of satellite cell migration.…”

From the Matrix to the Nucleus and Back: Mechanobiology in the Light of Health, Pathologies, and Regeneration of Oral Periodontal Tissues

“…Via the hydrolysis of ATP, these motor proteins can actively move along actin filaments [81][82][83]. Besides functions in cargo transport, myosins can, therefore, generate tension and traction forces through the relative displacement of actin filaments [84][85][86][87]. This mechanism immediately explains that FAs are not only outside-in signaling platforms that transmit mechanical ECM signals into the cell, but that actomyosin-generated cytoskeletal forces can also be transmitted to the ECM with the help of integrins and their neighboring adaptor proteins.…”