Mechanoaccumulative Elements of the Mammalian Actin Cytoskeleton

• Published in: Current biology Vol. 26; no. 11; pp. 1473 - 1479
• Main Authors: Schiffhauer, Eric S., Luo, Tianzhi, Mohan, Krithika, Srivastava, Vasudha, Qian, Xuyu, Griffis, Eric R., Iglesias, Pablo A., Robinson, Douglas N.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 06.06.2016
• Subjects: Actin Cytoskeleton - metabolism; Actinin - metabolism; Animals; Filamins - metabolism; HEK293 Cells; HeLa Cells; Humans; Mice; Myosin Type II - metabolism; NIH 3T3 Cells
• ISSN: 0960-9822; 1879-0445; 1879-0445
• DOI: 10.1016/j.cub.2016.04.007

To change shape, divide, form junctions, and migrate, cells reorganize their cytoskeletons in response to changing mechanical environments [1–4]. Actin cytoskeletal elements, including myosin II motors and actin crosslinkers, structurally remodel and activate signaling pathways in response to imposed stresses [5–9]. Recent studies demonstrate the importance of force-dependent structural rearrangement of α-catenin in adherens junctions [10] and vinculin’s molecular clutch mechanism in focal adhesions [11]. However, the complete landscape of cytoskeletal mechanoresponsive proteins and the mechanisms by which these elements sense and respond to force remain to be elucidated. To find mechanosensitive elements in mammalian cells, we examined protein relocalization in response to controlled external stresses applied to individual cells. Here, we show that non-muscle myosin II, α-actinin, and filamin accumulate to mechanically stressed regions in cells from diverse lineages. Using reaction-diffusion models for force-sensitive binding, we successfully predicted which mammalian α-actinin and filamin paralogs would be mechanoaccumulative. Furthermore, a “Goldilocks zone” must exist for each protein where the actin-binding affinity must be optimal for accumulation. In addition, we leveraged genetic mutants to gain a molecular understanding of the mechanisms of α-actinin and filamin catch-bonding behavior. Two distinct modes of mechanoaccumulation can be observed: a fast, diffusion-based accumulation and a slower, myosin II-dependent cortical flow phase that acts on proteins with specific binding lifetimes. Finally, we uncovered cell-type- and cell-cycle-stage-specific control of the mechanosensation of myosin IIB, but not myosin IIA or IIC. Overall, these mechanoaccumulative mechanisms drive the cell’s response to physical perturbation during proper tissue development and disease. •α-actinin, filamin, and myosin II paralogs are major mechanoaccumulative proteins•Dictyostelium-developed models predict mammalian paralog-specific mechanoresponses•Diffusion-mediated accumulation can be separated from myosin II-driven flow•Cooperativity and catch bonds define a “Goldilocks zone” for mechanoaccumulation The actin cytoskeleton controls cellular shape change during normal development and in disease processes. Schiffhauer et al. discover mammalian cytoskeletal proteins that accumulate in response to stress and outline molecular mechanisms driving this accumulation. These proteins comprise the cell’s network-scale response to control cell shape.