title: A mechanical-biochemical feedback loop regulates remodeling in the actin cytoskeleton.
abstract: Cytoskeletal actin assemblies transmit mechanical stresses that molecular sensors transduce into biochemical signals to trigger cytoskeletal remodeling and other downstream events. How mechanical and biochemical signaling cooperate to orchestrate complex remodeling tasks has not been elucidated. Here, we studied remodeling of contractile actomyosin stress fibers. When fibers spontaneously fractured, they recoiled and disassembled actin synchronously. The disassembly rate was accelerated more than twofold above the resting value, but only when contraction increased the actin density to a threshold value following a time delay. A mathematical model explained this as originating in the increased overlap of actin filaments produced by myosin II-driven contraction. Above a threshold overlap, this mechanical signal is transduced into accelerated disassembly by a mechanism that may sense overlap directly or through associated elastic stresses. This biochemical response lowers the actin density, overlap, and stresses. The model showed that this feedback mechanism, together with rapid stress transmission along the actin bundle, spatiotemporally synchronizes actin disassembly and fiber contraction. Similar actin remodeling kinetics occurred in expanding or contracting intact stress fibers but over much longer timescales. The model accurately described these kinetics, with an almost identical value of the threshold overlap that accelerates disassembly. Finally, we measured resting stress fibers, for which the model predicts constant actin overlap that balances disassembly and assembly. The overlap was indeed regulated, with a value close to that predicted. Our results suggest that coordinated mechanical and biochemical signaling enables extended actomyosin assemblies to adapt dynamically to the mechanical stresses they convey and direct their own remodeling.
authors.affiliation: Departments of Chemical Engineering.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Stachowiak
authors.affiliation: Departments of Biology and Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
authors.affiliation: Departments of Biology and Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Blankman
authors.affiliation: Departments of Biology and Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Chapin
authors.affiliation: Applied Physics and Applied Mathematics, and.
authors.forename: Hayri E
authors.identifier: http://orcid.org/0000-0002-0225-0180
authors.initials: HE
authors.lastname: Balcioglu
authors.affiliation: Physics, Columbia University, New York, NY 10027; and.
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Departments of Biology and Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112 bo8@columbia.edu mary.beckerle@hci.utah.edu.
authors.forename: Mary C
authors.initials: MC
authors.lastname: Beckerle
authors.affiliation: Departments of Chemical Engineering, bo8@columbia.edu mary.beckerle@hci.utah.edu.
authors.forename: Ben
authors.initials: B
authors.lastname: O'Shaughnessy
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000185:Actinin / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000205:Actomyosin / Q000378:metabolism; D000818:Animals; D004548:Elasticity; D025461:Feedback, Physiological; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008853:Microscopy; D008962:Models, Theoretical; D009119:Muscle Contraction; D015398:Signal Transduction; D013997:Time Factors; D060589:Zyxin / Q000378:metabolism
chemical_list: D000199:Actins; C498285:Zyx protein, mouse; D060589:Zyxin; D000185:Actinin; D000205:Actomyosin
keywords: contractility; cytoskeleton; mechanotransduction; mechanotransmission; stress fibers