Sensing their plasma membrane curvature allows migrating cells to circumvent obstacles

Abstract

Cell migration is fundamental for the immune response, development, and morphogenesis. For navigation through complex and ever-changing environments, migrating cells require a balance between a stable leading-edge, which is necessary for directional migration, and some unstable features to enable the required dynamic behaviors. The leading edge is often composed of actin-driven protrusions including lamellipodia and ruffles with continuously changing membrane curvature. Whether their membrane topography affects the cell's leading edge and motion persistence in complex environments remains unknown. To study this, we combined a theoretical analysis with machine learning-based segmentation for time-resolved TIRF microscopy, membrane topography analysis from electron microscopy images and microfluidics. We discovered that cell motion persistence and directionality, in both freely moving and environmentally-constrained cells, strongly depend on the curvature-sensing protein Snx33. Specifically, Snx33 promotes leading edge instabilities by locally inhibiting WAVE2- driven actin polymerization in a curvature-dependent manner. Snx33 knockout cells migrate faster and are more persistent during unobstructed migration, but fail when a change in direction is required. Thus, Snx33 is key for steering cell motility in complex environments by facilitating contact inhibition of locomotion and promoting efficient turning. These results identify cell surface topography as an organizing principle at the cell periphery that directs cell migration.

Theoretical model of membrane protrusions driven by curved active proteins

“…5Aii). The texture of these clusters seems similar to the membrane ruffles observed in [20] behind the leading edge of motile cells. In this work, the ruffles were attributed to the interaction between concave and convex membrane proteins, that are also involved in the recruitment of the actin polymerization.…”

“…Our mixtures of CMC of opposite curvatures (Figs. 4C,5) gives rise to membrane shapes that resemble in their texture the ruffles observed in cells [20]. In addition, we find that when the passive concave component is highly curved, we observe a phase separation within the CMC clusters, whereby the concave CMC forms an internalized spherical invagination.…”

“…In addition, we implement optional models of inhibition of the force on the CMC by neighbors, based on [20] which shows different protein species can inhibit the activity of polymerization, inhibiting the actin recruitment and thus force on the CMCs. We implement a proportional inhibition, where an active (1) and inhibiting (2) CMC species exist…”

Curvature in Biological Systems: Its Quantification, Emergence, and Implications across the Scales

“…[ 142 ] A recent study also reported Snx33, a curvature‐sensing protein located at the leading edge of a cell membrane, as a determinant of actin‐driven cell migration on curved surfaces. [ 143 ] Using serrated channels with curvature radii much smaller than the size of a cell, nonadhesive cells were also found to use small‐scale topographical cues to propel themselves following a minimal model of active actomyosin flows on curved substrates. [ 144 ]…”

“…[142] A recent study also reported Snx33, a curvature-sensing protein located at the leading edge of a cell membrane, as a determinant of actin-driven cell migration on curved surfaces. [143] Using serrated channels with curvature radii much smaller than the size of a cell, nonadhesive cells were also found to use smallscale topographical cues to propel themselves following a minimal model of active actomyosin flows on curved substrates. [144] Curvature-driven cell behavior also involves the nucleus as a mechanotransducer, which experiences changes in cell shape through the transmission of mechanical deformations from the cell membrane to the nuclear membrane via different cytoskeletal filaments like actin, microtubule, or intermediate filaments (see glossary).…”