Myosin IIB assembly state determines its mechanosensitive dynamics

Abstract

Dynamical cell shape changes require a highly sensitive cellular system that can respond to chemical and mechanical inputs. Myosin IIs are key players in the cell’s ability to react to mechanical inputs, demonstrating an ability to accumulate in response to applied stress. Here, we show that inputs that influence the ability of myosin II to assemble into filaments impact the ability of myosin to respond to stress in a predictable manner. Using mathematical modeling for Dictyostelium myosin II, we predict that myosin II mechanoresponsiveness will be biphasic with an optimum established by the percentage of myosin II assembled into bipolar filaments. In HeLa and NIH 3T3 cells, heavy chain phosphorylation of NMIIB by PKCζ, as well as expression of NMIIA, can control the ability of NMIIB to mechanorespond by influencing its assembly state. These data demonstrate that multiple inputs to the myosin II assembly state integrate at the level of myosin II to govern the cellular response to mechanical inputs.

Linking the Landscape of MYH9-Related Diseases to the Molecular Mechanisms that Control Non-Muscle Myosin II-A Function in Cells

“…Visualization of GFP-MHCII-A in live cells revealed continuous assembly and disassembly during membrane protrusion [16]. The other two paralogs, NMII-B and NMII-C are kinetically better suited for force, strain and structure buildup in non-muscle cells [17,18]. As such, their assembly and turnover are much slower [19,20].…”

Precise tuning of cortical contractility regulates cell shape during cytokinesis

“…Indeed, organisms such as Dictyostelium and adhesive cell lines such as normal rat kidney (NRK) cells can divide without MII activity (Kanada et al, 2005;Neujahr et al, 1997). Another mechanism recently proposed could involve regulating the amount of each paralog that can assemble into filaments, for instance through PKC activity (Schiffhauer et al, 2019). Finally, oscillations of upstream regulators of MII, which appear to be evolutionarily conserved, and has been observed from flies to mammals (Bement et al, 2015;Machacek et al, 2009;Martin et al, 2009), could regulate the level of MII activation.…”

How the mechanobiome drives cell behavior, viewed through the lens of control theory

“…IIB assembly, manipulation of the serine 1935 residue or PKCζ kinase, which phosphorylates this residue, is sufficient to shift the systems towards the 20% myosin IIB assembly, increasing its mechanoresponse (Fig. 2D) (Schiffhauer et al, 2019). This example illustrates how protein post-translational modification, phosphorylation in this case, can be used by cells to control the setpoint.…”

“…To ensure robust cellular mechanical behaviors, the cytoskeletal network functions as a control system (see Box 1), which includes sensors to detect environmental cues or deviations away from a desired behavior, and actuators, which execute the desired behavior or process ( Fig. 2A) (Ren et al, 2009;Kee et al, 2012;Srivastava and Robinson, 2015;Srivastava et al, 2016;Schiffhauer and Robinson, 2017;Schiffhauer et al, 2019). Inherently, control systems may be open-or close-looped.…”

“…Setpoint control also provides insight into the functions and behaviors of different cell types. The baseline fraction of assembly of non-muscle myosin IIB into bipolar thick filaments (BTFs) predicts its mechanoresponsive ability across a wide range of cell types, including NIH 3T3 fibroblasts, HeLa and Jurkat cells (Schiffhauer et al, 2019). The mechanism underlying this setpoint control depends upon phosphorylation of the myosin heavy chain, which serves to maintain the particular ratio of unassembled (free) to assembled (bipolar filaments) myosin IIB subunits for each cell type.…”