A tug of war between filament treadmilling and myosin induced contractility generates actin rings
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Evaluation Summary:
This important paper uses molecular simulations to explain how actomyosin networks transition from small clusters to the cortex or ring-shaped actin networks. The authors provide compelling evidence that variation in filament turnover rate and myosin concentration triggers a phase transition of these networks. The predictions of this model are consistent with observations made in T cells, where actin ring formation can be induced following their activation by antibodies.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Abstract
In most eukaryotic cells, actin filaments assemble into a shell-like actin cortex under the plasma membrane, controlling cellular morphology, mechanics, and signaling. The actin cortex is highly polymorphic, adopting diverse forms such as the ring-like structures found in podosomes, axonal rings, and immune synapses. The biophysical principles that underlie the formation of actin rings and cortices remain unknown. Using a molecular simulation platform called MEDYAN, we discovered that varying the filament treadmilling rate and myosin concentration induces a finite size phase transition in actomyosin network structures. We found that actomyosin networks condense into clusters at low treadmilling rates or high myosin concentrations but form ring-like or cortex-like structures at high treadmilling rates and low myosin concentrations. This mechanism is supported by our corroborating experiments on live T cells, which exhibit ring-like actin networks upon activation by stimulatory antibody. Upon disruption of filament treadmilling or enhancement of myosin activity, the pre-existing actin rings are disrupted into actin clusters or collapse towards the network center respectively. Our analyses suggest that the ring-like actin structure is a preferred state of low mechanical energy, which is, importantly, only reachable at sufficiently high treadmilling rates.
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Evaluation Summary:
This important paper uses molecular simulations to explain how actomyosin networks transition from small clusters to the cortex or ring-shaped actin networks. The authors provide compelling evidence that variation in filament turnover rate and myosin concentration triggers a phase transition of these networks. The predictions of this model are consistent with observations made in T cells, where actin ring formation can be induced following their activation by antibodies.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
The authors are trying to show that transitions between ring-like structures and clusters are driven by the balance between 2 main forces: filament treadmilling and motor protein-driven contractility. The results obtained in computer simulations are always compared with properly set experiments, making the story very convincing. In addition, the possible microscopic picture of the mechanisms is provided, although at a more phenomenological level. But given the complexity of the system, I find it very appropriate.
One of the most important achievements of this work is that the authors clearly identified and proved the factors that lead to a very non-trivial behavior. This should stimulate more work on understanding what biological regulation mechanisms might be involved in these phenomena.
I believe that this …
Reviewer #1 (Public Review):
The authors are trying to show that transitions between ring-like structures and clusters are driven by the balance between 2 main forces: filament treadmilling and motor protein-driven contractility. The results obtained in computer simulations are always compared with properly set experiments, making the story very convincing. In addition, the possible microscopic picture of the mechanisms is provided, although at a more phenomenological level. But given the complexity of the system, I find it very appropriate.
One of the most important achievements of this work is that the authors clearly identified and proved the factors that lead to a very non-trivial behavior. This should stimulate more work on understanding what biological regulation mechanisms might be involved in these phenomena.
I believe that this work will have a strong impact in the field. I am especially impressed by the successful combination of advanced computational and experimental methods.
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Reviewer #2 (Public Review):
In this article, the authors aim at understanding how the possible phases of actin networks (here: rings versus patches in contractile actin) form according to the network biochemistry, namely the number of motors and the filament turnover rate.
They compare simulation predictions to experiments in T cells where an actin ring can be observed after cell spreading on glass.
This paper is an important effort to address the key issue of control of actin networks. It uses convincingly a simulation method to yield interesting insight into the system. The methods are well documented and most results are convincing.
A weakness is the lack of control information for some of the simulations. Additionally, some observations on the ring width are confusing, and the comparison between experiments and simulations is not …
Reviewer #2 (Public Review):
In this article, the authors aim at understanding how the possible phases of actin networks (here: rings versus patches in contractile actin) form according to the network biochemistry, namely the number of motors and the filament turnover rate.
They compare simulation predictions to experiments in T cells where an actin ring can be observed after cell spreading on glass.
This paper is an important effort to address the key issue of control of actin networks. It uses convincingly a simulation method to yield interesting insight into the system. The methods are well documented and most results are convincing.
A weakness is the lack of control information for some of the simulations. Additionally, some observations on the ring width are confusing, and the comparison between experiments and simulations is not so clear-cut. The final conclusion of the system as trapped in a meta-stable state seems a bit overstated. Lastly, a qualitative understanding of the physical mechanism leading to ring formation rather than patch could be a great addition.
This is important work for the field as the control of the actin network phase is still largely elusive. The results are thus highly interesting. The numerical methods are plagued by an over-restrictive license, crippling its potential adoption by the community.
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