Compartmentalized Cytoplasmic Flows Direct Protein Transport to the Cell’s Leading Edge
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Abstract
Inside the cell, proteins essential for signaling, morphogenesis, and migration navigate complex pathways, typically via vesicular trafficking or microtubule-driven mechanisms 1–3 . However, the process by which soluble cytoskeletal monomers maneuver through the cytoplasm’s ever-changing environment to reach their destinations without using these pathways remains unknown. 4–6 Here, we show that actin cytoskeletal treadmilling leads to the formation of a semi-permeable actin-myosin barrier, creating a specialized compartment separated from the rest of the cell body that directs proteins toward the cell edge by advection, diffusion facilitated by fluid flow. Contraction at this barrier generates a molecularly non-specific fluid flow that transports actin, actin-binding proteins, adhesion proteins, and even inert proteins forward. The local curvature of the barrier specifically targets these proteins toward protruding edges of the leading edge, sites of new filament growth, effectively coordinating protein distribution with cellular dynamics. Outside this compartment, diffusion remains the primary mode of protein transport, contrasting sharply with the directed advection within. This discovery reveals a novel protein transport mechanism that redefines the front of the cell as a pseudo-organelle, actively orchestrating protein mobilization for cellular front activities such as protrusion and adhesion. By elucidating a new model of protein dynamics at the cellular front, this work contributes a critical piece to the puzzle of how cells adapt their internal structures for targeted and rapid response to extracellular cues. The findings challenge the current understanding of intracellular transport, suggesting that cells possess highly specialized and previously unrecognized organizational strategies for managing protein distribution efficiently, providing a new framework for understanding the cellular architecture’s role in rapid response and adaptation to environmental changes.
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Photo-activation of a diffraction-limited spot in a CAD cell expressing PaGFPactin shows asymmetricmovement toward the front of the cell.
This text appears to be the same as that describing panel a. Is this intended? I assume C is an image of a blebbistatin experiment?
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The EGFP-actin network of NG108 cells was rapidly bleached between 0.3 and 1.3s. At3.9s, bleached actin monomer from the network has been transported (recycled) to the front ofthe cell, repolymerized at the leading edge, and traveled rearward (thin dark line indicated byarrow).
Out of curiosity (and ignorance) why is the line containing the repolymerized bleached monomer so thin? The volume of bleached monomer appears to be large. Is the width of the repolymerized line impacted by the relative position of the bleaching?
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P values from Scheffe post-ANOVA show no significant difference between blebbistatin and Y27632 treatments either parallel or perpendicular to the edge and no significant difference between the conditions parallel to the edge
Was the F statistic from the ANOVA significant and were the comparisons actually between drug treatment and the control? If so, I would think a Tukey's post-hoc test would be more appropriate. If the ANOVA was not significant, then why are none of the p values from the Sheffe post-hoc test not significant? I was suprised because it looks like in panel d that the control and treatments look different.
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In summary, our findings reconceptualize the front of the cell as a dynamic, ‘membrane-less’ organelle 35, which perpetually directs polymerizable proteins to precisely where they are most needed
Wow, this is a really important finding that reshapes how we think about cells can efficiently and rapidly alter their architecture in response to environmental changes.
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