Mechanoregulated inhibition of formin facilitates contractile actomyosin ring assembly

Dennis Zimmermann; Kaitlin E. Homa; Glen M. Hocky; Luther W. Pollard; Enrique M. De La Cruz; Gregory A. Voth; Kathleen M. Trybus; David R. Kovar

doi:10.1038/s41467-017-00445-3

Mechanoregulated inhibition of formin facilitates contractile actomyosin ring assembly

Dennis Zimmermann, Kaitlin E. Homa, Glen M. Hocky, Luther W. Pollard, Enrique M. De La Cruz, Gregory A. Voth, Kathleen M. Trybus, David R. Kovar

Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

Cytokinesis physically separates dividing cells by forming a contractile actomyosin ring. The fission yeast contractile ring has been proposed to assemble by Search-Capture-Pull-Release from cytokinesis precursor nodes that include the molecular motor type-II myosin Myo2 and the actin assembly factor formin Cdc12. By successfully reconstituting Search-Capture-Pull in vitro, we discovered that formin Cdc12 is a mechanosensor, whereby myosin pulling on formin-bound actin filaments inhibits Cdc12-mediated actin assembly. We mapped Cdc12 mechanoregulation to its formin homology 1 domain, which facilitates delivery of new actin subunits to the elongating actin filament. Quantitative modeling suggests that the pulling force of the myosin propagates through the actin filament, which behaves as an entropic spring, and thereby may stretch the disordered formin homology 1 domain and impede formin-mediated actin filament elongation. Finally, live cell imaging of mechano-insensitive formin mutant cells established that mechanoregulation of formin Cdc12 is required for efficient contractile ring assembly in vivo.

Original language	English (US)
Article number	703
Journal	Nature communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-00445-3
State	Published - Dec 1 2017

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-017-00445-3

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title = "Mechanoregulated inhibition of formin facilitates contractile actomyosin ring assembly",

abstract = "Cytokinesis physically separates dividing cells by forming a contractile actomyosin ring. The fission yeast contractile ring has been proposed to assemble by Search-Capture-Pull-Release from cytokinesis precursor nodes that include the molecular motor type-II myosin Myo2 and the actin assembly factor formin Cdc12. By successfully reconstituting Search-Capture-Pull in vitro, we discovered that formin Cdc12 is a mechanosensor, whereby myosin pulling on formin-bound actin filaments inhibits Cdc12-mediated actin assembly. We mapped Cdc12 mechanoregulation to its formin homology 1 domain, which facilitates delivery of new actin subunits to the elongating actin filament. Quantitative modeling suggests that the pulling force of the myosin propagates through the actin filament, which behaves as an entropic spring, and thereby may stretch the disordered formin homology 1 domain and impede formin-mediated actin filament elongation. Finally, live cell imaging of mechano-insensitive formin mutant cells established that mechanoregulation of formin Cdc12 is required for efficient contractile ring assembly in vivo.",

author = "Dennis Zimmermann and Homa, {Kaitlin E.} and Hocky, {Glen M.} and Pollard, {Luther W.} and {De La Cruz}, {Enrique M.} and Voth, {Gregory A.} and Trybus, {Kathleen M.} and Kovar, {David R.}",

note = "Funding Information: We thank Matthew Lord for helping to conceptualize this project. We thank Jan{\'e} Kondev (Brandeis University) for extremely helpful discussions concerning force propagation mechanisms through entropic springs. We also thank members of the Kovar and Trybus labs for reagents and helpful discussions. This research was supported by DOD/ARO through a MURI grant, number W911NF1410403, on which G.A.V., E.M.D.L.C. and D.R.K. are co-investigators. This work was also supported by a DFG (German Research Foundation) Postdoctoral Research Fellowship Zi 1496/2-1 (to D.Z.), NIH Molecular and Cellular Biology Training grant T32 GM007183 (to K.E.H.), NIH Ruth L. Kirschstein NRSA F32 GM113415-01 (to G.M.H.), and R01 GM078097 to (K.M.T.). Publisher Copyright: {\textcopyright} 2017 The Author(s).",

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doi = "10.1038/s41467-017-00445-3",

language = "English (US)",

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AU - Zimmermann, Dennis

AU - Homa, Kaitlin E.

AU - Hocky, Glen M.

AU - Pollard, Luther W.

AU - De La Cruz, Enrique M.

AU - Voth, Gregory A.

AU - Trybus, Kathleen M.

AU - Kovar, David R.

N1 - Funding Information: We thank Matthew Lord for helping to conceptualize this project. We thank Jané Kondev (Brandeis University) for extremely helpful discussions concerning force propagation mechanisms through entropic springs. We also thank members of the Kovar and Trybus labs for reagents and helpful discussions. This research was supported by DOD/ARO through a MURI grant, number W911NF1410403, on which G.A.V., E.M.D.L.C. and D.R.K. are co-investigators. This work was also supported by a DFG (German Research Foundation) Postdoctoral Research Fellowship Zi 1496/2-1 (to D.Z.), NIH Molecular and Cellular Biology Training grant T32 GM007183 (to K.E.H.), NIH Ruth L. Kirschstein NRSA F32 GM113415-01 (to G.M.H.), and R01 GM078097 to (K.M.T.). Publisher Copyright: © 2017 The Author(s).

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Cytokinesis physically separates dividing cells by forming a contractile actomyosin ring. The fission yeast contractile ring has been proposed to assemble by Search-Capture-Pull-Release from cytokinesis precursor nodes that include the molecular motor type-II myosin Myo2 and the actin assembly factor formin Cdc12. By successfully reconstituting Search-Capture-Pull in vitro, we discovered that formin Cdc12 is a mechanosensor, whereby myosin pulling on formin-bound actin filaments inhibits Cdc12-mediated actin assembly. We mapped Cdc12 mechanoregulation to its formin homology 1 domain, which facilitates delivery of new actin subunits to the elongating actin filament. Quantitative modeling suggests that the pulling force of the myosin propagates through the actin filament, which behaves as an entropic spring, and thereby may stretch the disordered formin homology 1 domain and impede formin-mediated actin filament elongation. Finally, live cell imaging of mechano-insensitive formin mutant cells established that mechanoregulation of formin Cdc12 is required for efficient contractile ring assembly in vivo.

AB - Cytokinesis physically separates dividing cells by forming a contractile actomyosin ring. The fission yeast contractile ring has been proposed to assemble by Search-Capture-Pull-Release from cytokinesis precursor nodes that include the molecular motor type-II myosin Myo2 and the actin assembly factor formin Cdc12. By successfully reconstituting Search-Capture-Pull in vitro, we discovered that formin Cdc12 is a mechanosensor, whereby myosin pulling on formin-bound actin filaments inhibits Cdc12-mediated actin assembly. We mapped Cdc12 mechanoregulation to its formin homology 1 domain, which facilitates delivery of new actin subunits to the elongating actin filament. Quantitative modeling suggests that the pulling force of the myosin propagates through the actin filament, which behaves as an entropic spring, and thereby may stretch the disordered formin homology 1 domain and impede formin-mediated actin filament elongation. Finally, live cell imaging of mechano-insensitive formin mutant cells established that mechanoregulation of formin Cdc12 is required for efficient contractile ring assembly in vivo.

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Mechanoregulated inhibition of formin facilitates contractile actomyosin ring assembly

Abstract

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