Mechanically induced topological transition of spectrin regulates its distribution in the mammalian cortex

Abstract

The cell cortex is a dynamic assembly formed by the plasma membrane and the underlying cytoskeleton. As the main determinant of cell shape, the cortex ensures its integrity during passive deformation or active response by adapting cytoskeleton topologies with poorly understood mechanisms. The spectrin meshwork ensures such adaptation in erythrocytes and neurons by adopting dramatically different organizations. Erythrocytes rely on triangular-like lattices of spectrin tetramers, which in neurons are organized in parallel and periodic arrays. Since spectrin is ubiquitously expressed, we exploited Expansion Microscopy to discover that these two distinct topologies can co-exist in other mammalian cells such as fibroblasts. We show through biophysical measurements and computational modeling that spectrin provides coverage of the cortex and, with the intervention of actomyosin, erythroid-like lattices can dynamically transition into condensates that resemble neuron-like periodic arrays fenced by actin stress fibers. Spectrin condensates experience lower mechanical stress and turnover despite displaying an extension close to the contour length of the tetramer. Our study sheds light on the adaptive properties of spectrin, which ensures protection of the cortex by undergoing mechanically induced topological transitions.

Dynamic mechanisms for membrane skeleton transitions

“…We run the simulations in MATLAB R2021a desktop computer. Following (11), for the patch of actin-spectrin meshwork (Figs. [3][4][5][6], we obtain the initial spectrin mesh with the MATLAB's delaunayTriangulation.m function and implement the forward Euler method to solve Eq.…”

“…showed that the distribution of spectrin is dynamic and it changes during mechanical challenges like cell adhesion, contraction, compression, stretch, and osmolarity changes ( 10 ). Moreover, recent studies from our group revealed that βII-spectrin transitions between a RBC-like configuration to a periodic axonal configuration in fibroblasts ( 11 ). Such a transition is driven by actomyosin contractility.…”

“…The unfolding of the repeats depends on the force and velocity of the pulling (1,8). The structural organization of the spectrin scaffold depends on the cell type (9) and as shown more recently, on subcellular location (10,11). In red blood cells, the two main paralogues of spectrin, αI and βI, associate laterally and in an antiparallel manner to form long and flexible heterodimers (6,12).…”

“…In this work, we sought to understand how a minimal system of short actin filaments, myosin motors, and spectrin tetramers can give rise to a wide range of net-work configurations and confer mechanoprotective capabilities in the cellular context. We used a network model of springs and cables to represent the membrane skeleton (11,(20)(21)(22)(23) (Fig. 1 E-F) and incorporated the response of the membrane to mechanical stress (24).…”

“…Myosin may also span individual rings providing contraction ( 15 ). D ) In fibroblasts, the actin-spectrin meshwork has a heterogeneous and dynamic configuration ( 11 ). E ) Schematic of the simulated 3D network model.…”