Actin Retrograde Flow Research Articles

Ctdnep1 and Eps8L2 regulate dorsal actin cables for nuclear positioning during cell migration

SummaryCells actively position their nuclei within the cytoplasm for multiple cellular and physiological functions.1, 2, 3 Consequently, nuclear mispositioning is usually associated with cell dysfunction and disease, from muscular disorders to cancer metastasis.4, 5, 6, 7 Different cell types position their nuclei away from the leading edge during cell migration.8, 9, 10, 11 In migrating fibroblasts, nuclear positioning is driven by an actin retrograde flow originated at the leading edge that drives dorsal actin cables away from the leading edge. The dorsal actin cables connect to the nuclear envelope by the linker of nucleoskeleton and cytoskeleton (LINC) complex on transmembrane actin-associated nuclear (TAN) lines.12, 13, 14 Dorsal actin cables are required for the formation of TAN lines. How dorsal actin cables are organized to promote TAN lines formation is unknown. Here, we report a role for Ctdnep1/Dullard, a nuclear envelope phosphatase,15, 16, 17, 18, 19, 20, 21, 22 and the actin regulator Eps8L223, 24, 25 on nuclear positioning and cell migration. We demonstrate that Ctdnep1 and Eps8L2 directly interact, and this interaction is important for nuclear positioning and cell migration. We also show that Ctdnep1 and Eps8L2 are involved in the formation and thickness of dorsal actin cables required for TAN lines engagement during nuclear movement. We propose that Ctdnep1-Eps8L2 interaction regulates dorsal actin cables for nuclear movement during cell migration.

Polymer Nanopillars Induce Increased Paxillin Adhesion Assembly and Promote Axon Growth in Primary Cortical Neurons

AbstractThe complexity of the extracellular matrix consists of micro‐ and nanoscale structures that influence neuronal development through contact guidance. Substrates with defined topographic cues mimic the complex extracellular environment and can improve the interface between cells and biomedical devices as well as potentially serve as tissue engineering scaffolds. This study investigates axon development and growth of primary cortical neurons on OrmoComp nanopillars of various dimensions. Neuronal somas and neurites form adhesions and F‐actin accumulations around the pillars indicating a close contact to the topography. In addition, higher pillars (400 nm) confine the growing neurites, resulting in greater neurite alignment to the topographical pattern compared to lower pillars (100 nm). A comprehensive analysis of growth cone dynamics during axon development shows that nanopillars induce earlier axon establishment and change the periodicity of growth cone dynamics by promoting elongation. This results in longer axons compared to the flat substrate. Finally, the increase in surface area available for growth cone coupling provided by nanopillar sidewalls is correlated with increased assembly of paxillin‐rich point contact adhesions and a reduction in actin retrograde flow rates allowing for accelerated and persistent neurite outgrowth.

One-dimensional cell motility patterns

During migration cells exhibit a rich variety of seemingly random migration patterns, which makes unraveling the underlying mechanisms that control cell migration a daunting challenge. For efficient migration cells require a mechanism for polarization, so that traction forces are produced in the direction of motion, while adhesion is released to allow forward migration. To simplify the study of this process cells have been studied when placed along one-dimensional tracks, where single cells exhibit both smooth and stick-slip migration modes. The stick-slip motility mode is characterized by protrusive motion at the cell front, coupled with slow cell elongation, which is followed by rapid retractions of the cell back. In this study, we explore a minimal physical model that couples the force applied on the adhesion bonds to the length variations of the cell and the traction forces applied by the polarized actin retrograde flow. We show that the rich spectrum of cell migration patterns emerges from this model as different \emph{deterministic} dynamical phases. This result suggests a source for the large cell-to-cell variability (CCV) in cell migration patterns observed in single cells over time and within cell populations. The large heterogeneity can arise from small fluctuations in the cellular components that are greatly amplified due to moving the cells' internal state across the dynamical phase transition lines. Temporal noise is shown to drive random changes in the cellular polarization direction, which is enhanced during the stick-slip migration mode. These results offer a new framework to explain experimental observations of migrating cells, resulting from noisy switching between underlying deterministic migration modes.

The WAVE Regulatory Complex Is Required to Balance Protrusion and Adhesion in Migration.

Cells migrating over 2D substrates are required to polymerise actin at the leading edge to form lamellipodia protrusions and nascent adhesions to anchor the protrusion to the substrate. The major actin nucleator in lamellipodia formation is the Arp2/3 complex, which is activated by the WAVE regulatory complex (WRC). Using inducible Nckap1 floxed mouse embryonic fibroblasts (MEFs), we confirm that the WRC is required for lamellipodia formation, and importantly, for generating the retrograde flow of actin from the leading cell edge. The loss of NCKAP1 also affects cell spreading and focal adhesion dynamics. In the absence of lamellipodium, cells can become elongated and move with a single thin pseudopod, which appears devoid of N-WASP. This phenotype was more prevalent on collagen than fibronectin, where we observed an increase in migratory speed. Thus, 2D cell migration on collagen is less dependent on branched actin.

Cellular locomotion using environmental topography.

Eukaryotic cells migrate by coupling the intracellular force of the actin cytoskeleton to the environment. While force coupling is usually mediated by transmembrane adhesion receptors, especially those of the integrin family, amoeboid cells such as leukocytes can migrate extremely fast despite very low adhesive forces1. Here we show that leukocytes cannot only migrate under low adhesion but can also transmit forces in the complete absence of transmembrane force coupling. When confined within three-dimensional environments, they use the topographical features of the substrate to propel themselves. Here the retrograde flow of the actin cytoskeleton follows the texture of the substrate, creating retrograde shear forces that are sufficient to drive the cell body forwards. Notably, adhesion-dependent and adhesion-independent migration are not mutuallyexclusive, but rather are variants of the same principle of coupling retrograde actin flow to the environment and thus can potentially operate interchangeably and simultaneously. As adhesion-free migration is independent of the chemical composition of the environment, it renders cells completely autonomous in their locomotive behaviour.

Profilin 1 delivery tunes cytoskeletal dynamics toward CNS axon regeneration

After trauma, regeneration of adult CNS axons is abortive, causing devastating neurologic deficits. Despite progress in rehabilitative care, there is no effective treatment that stimulates axonal growth following injury. Using models with different regenerative capacities, followed by gain- and loss-of-function analysis, we identified profilin 1 (Pfn1) as a coordinator of actin and microtubules (MTs), powering axonal growth and regeneration. In growth cones, Pfn1 increased actin retrograde flow, MT growth speed, and invasion of filopodia by MTs, orchestrating cytoskeletal dynamics toward axonal growth. In vitro, active Pfn1 promoted MT growth in a formin-dependent manner, whereas localization of MTs to growth cone filopodia was facilitated by direct MT binding and interaction with formins. In vivo, Pfn1 ablation limited regeneration of growth-competent axons after sciatic nerve and spinal cord injury. Adeno-associated viral (AAV) delivery of constitutively active Pfn1 to rodents promoted axonal regeneration, neuromuscular junction maturation, and functional recovery of injured sciatic nerves, and increased the ability of regenerating axons to penetrate the inhibitory spinal cord glial scar. Thus, we identify Pfn1 as an important regulator of axonal regeneration and suggest that AAV-mediated delivery of constitutively active Pfn1, together with the identification of modulators of Pfn1 activity, should be considered to treat the injured nervous system.

Agility in Mechanochemical Cellular Responses: Spatially-Localized Coupling of Cellular Control Modulates Traction Stresses and Retrograde Flow Within Cells

While there have been numerous studies of cell spreading on substrates with different stiffnesses that have helped to elucidate the role of the actin cytoskeleton in cell protrusion and in focal adhesion (FA) evolution, there are still several questions that remain unanswered. Specifically, we focus on the effects of substrate stiffness on modulating the coupling between protrusive activity and actin retrograde flow and investigate how quantitative changes in this coupling modify actin dynamics, FA evolution, and cell spread areas. This will allow us to better understand effect of substrate stiffness on the biphasic relationship between retrograde flow and traction stresses observed by Gardel et al. (JCB, 2008). We present an axisymmetric model of a flat cell spreading on a two-dimensional substrate. The actin network is modeled as a viscous gel, and actin spreading and contraction dynamics are incorporated into the model as a local active rate of deformation. The model also incorporates stress-dependent FA dynamics, which in turn modulate a cell's protrusive activity and speed of actin retrograde flow, thereby controlling the spreading rate. Using this model, we are able to recapitulate the three phases of cell spreading dynamics described in Gianonne et al. (Cell, 2004), and we predict how the balance of protrusive activity, retrograde flow, FA strength, and local actomyosin contractions must change as the cell evolves through these three phases. We also show that increases in substrate stiffness lead to changes in retrograde flow rates and myosin concentrations, which can affect the localization of the biphasic relationship between retrograde flow rates and traction stresses as well as affecting the size and strength of FAs.

Vangl2 acts at the interface between actin and N-cadherin to modulate mammalian neuronal outgrowth.

Dynamic mechanical interactions between adhesion complexes and the cytoskeleton are essential for axon outgrowth and guidance. Whether planar cell polarity (PCP) proteins, which regulate cytoskeleton dynamics and appear necessary for some axon guidance, also mediate interactions with membrane adhesion is still unclear. Here we show that Vangl2 controls growth cone velocity by regulating the internal retrograde actin flow in an N-cadherin-dependent fashion. Single molecule tracking experiments show that the loss of Vangl2 decreased fast-diffusing N-cadherin membrane molecules and increased confined N-cadherin trajectories. Using optically manipulated N-cadherin-coated microspheres, we correlated this behavior to a stronger mechanical coupling of N-cadherin with the actin cytoskeleton. Lastly, we show that the spatial distribution of Vangl2 within the growth cone is selectively affected by an N-cadherin-coated substrate. Altogether, our data show that Vangl2 acts as a negative regulator of axonal outgrowth by regulating the strength of the molecular clutch between N-cadherin and the actin cytoskeleton.

Differential nanoscale organisation of LFA-1 modulates T-cell migration.

Effector T-cells rely on integrins to drive adhesion and migration to facilitate their immune function. The heterodimeric transmembrane integrin LFA-1 (αLβ2 integrin) regulates adhesion and migration of effector T-cells through linkage of the extracellular matrix with the intracellular actin treadmill machinery. Here, we quantified the velocity and direction of F-actin flow in migrating T-cells alongside single-molecule localisation of transmembrane and intracellular LFA-1. Results showed that actin retrograde flow positively correlated and immobile actin negatively correlated with T-cell velocity. Plasma membrane-localised LFA-1 forms unique nano-clustering patterns in the leading edge, compared to the mid-focal zone, of migrating T-cells. Deleting the cytosolic phosphatase PTPN22, loss-of-function mutations of which have been linked to autoimmune disease, increased T-cell velocity, and leading-edge co-clustering of pY397 FAK, pY416 Src family kinases and LFA-1. These data suggest that differential nanoclustering patterns of LFA-1 in migrating T-cells may instruct intracellular signalling. Our data presents a paradigm where T-cells modulate the nanoscale organisation of adhesion and signalling molecules to fine tune their migration speed, with implications for the regulation of immune and inflammatory responses.This article has an associated First Person interview with the first author of the paper.

Targeting Mechanoresponsive Proteins in Pancreatic Cancer: 4-Hydroxyacetophenone Blocks Dissemination and Invasion by Activating MYH14.

Metastasis is complex, involving multiple genetic, epigenetic, biochemical, and physical changes in the cancer cell and its microenvironment. Cells with metastatic potential are often characterized by altered cellular contractility and deformability, lending them the flexibility to disseminate and navigate through different microenvironments. We demonstrate that mechanoresponsiveness is a hallmark of pancreatic cancer cells. Key mechanoresponsive proteins, those that accumulate in response to mechanical stress, specifically nonmuscle myosin IIA (MYH9) and IIC (MYH14), α-actinin 4, and filamin B, were highly expressed in pancreatic cancer as compared with healthy ductal epithelia. Their less responsive sister paralogs-myosin IIB (MYH10), α-actinin 1, and filamin A-had lower expression differential or disappeared with cancer progression. We demonstrate that proteins whose cellular contributions are often overlooked because of their low abundance can have profound impact on cell architecture, behavior, and mechanics. Here, the low abundant protein MYH14 promoted metastatic behavior and could be exploited with 4-hydroxyacetophenone (4-HAP), which increased MYH14 assembly, stiffening cells. As a result, 4-HAP decreased dissemination, induced cortical actin belts in spheroids, and slowed retrograde actin flow. 4-HAP also reduced liver metastases in human pancreatic cancer-bearing nude mice. Thus, increasing MYH14 assembly overwhelms the ability of cells to polarize and invade, suggesting targeting the mechanoresponsive proteins of the actin cytoskeleton as a new strategy to improve the survival of patients with pancreatic cancer. SIGNIFICANCE: This study demonstrates that mechanoresponsive proteins become upregulated with pancreatic cancer progression and that this system of proteins can be pharmacologically targeted to inhibit the metastatic potential of pancreatic cancer cells.

Cyclical Phosphorylation of LRAP35a and Its Binder CLASP2 by GSK3β and CK1δ Regulates EB1-Dependent MT Dynamics in Cell Migration

Mammalian cell cytoskeletal reorganization for efficient directional movement requires tight coordination of actomyosin and microtubule networks. Here we show that LRAP35a potentiated microtubule stabilization by promoting CLASP2/EB1 interaction besides MRCK/MYO18A complex formation for retrograde actin flow. The alternate regulation of these two networks by LRAP35a was tightly regulated by a series of phosphorylation events that dictated its specificity. Sequential phosphorylation of LRAP35a by PKA and GSK3β initiated the association of LRAP35a with CLASP2, while subsequent binding and further phosphorylation by CK1δ induced their dissociation which would facilitate LRAP35a/MRCK association in driving lamellar actomyosin flow. Importantly, microtubule dynamics was directly moderated by CK1δ activity on CLASP2 to regulate GSK3β phosphorylation of the SxIP motifs that block EB1 binding, an event countered by LRAP35a interaction and its competition for CK1δ activity. This study thus reveals an essential role for LRAP35a in coordinating lamellar contractility and microtubule polarization in cell migration.

Stick-slip dynamics of migrating cells on viscoelastic substrates.

Stick-slip motion, a common phenomenon observed during crawling of cells, is found to be strongly sensitive to the substrate stiffness. Stick-slip behaviors have previously been investigated typically using purely elastic substrates. For a more realistic understanding of this phenomenon, we propose a theoretical model to study the dynamics on a viscoelastic substrate. Our model, based on a reaction-diffusion framework, incorporates known important interactions such as retrograde flow of actin, myosin contractility, force-dependent assembly, and disassembly of focal adhesions coupled with cell-substrate interaction. We show that consideration of a viscoelastic substrate not only captures the usually observed stick-slip jumps but also predicts the existence of an optimal substrate viscosity corresponding to maximum traction force and minimum retrograde flow which was hitherto unexplored. Moreover, our theory predicts the time evolution of individual bond force that characterizes the stick-slip patterns on soft versus stiff substrates. Our analysis also elucidates how the duration of the stick-slip cycles are affected by various cellular parameters.

Targeting non-muscle myosin II promotes corneal endothelial migration through regulating lamellipodial dynamics.

Corneal endothelial cell (CEC) dysfunction causes corneal edema that may lead to blindness. In addition to corneal transplantation, simple descemetorhexis has been proposed to treat centrally located disease with adequate peripheral cell reserve, but promoting the centripetal migration of CECs is pivotal to this strategy. Here, we show that targeting non-muscle myosin II (NMII) activity by Y27632, a ROCK inhibitor, or blebbistatin, a selective NMII inhibitor, promotes directional migration of CECs and accelerates in vitro wound healing. The lamellipodial protrusion persistence is increased, and actin retrograde flow is decreased after NMII inhibition. Counteracting lamellipodial protrusion by actin-related protein 2/3 (ARP2/3) inhibitor abolishes this migration-promoting effect. Although both Y27632 and blebbistatin accelerate wound healing, cell junctional integrity and barrier function are better preserved after blebbistatin treatment, leading to more rapid corneal deturgescence in rabbit corneal endothelial wounding model. Our findings indicate that NMII is a promising therapeutic target in the treatment of CEC dysfunction. KEY MESSAGES: NMII inhibition promotes directional migration and wound healing of CECs in vitro. Lamellipodial protrusion persistence is increased after NMII inhibition. Selective NMII inhibitor preserves junctional integrity better than ROCK inhibitor. Selective NMII inhibitor accelerates corneal deturgescence after wounding in vivo.

Cytoskeletal Control of Antigen-Dependent T Cell Activation

SummaryCytoskeletal actin dynamics is essential for T cell activation. Here, we show evidence that the binding kinetics of the antigen engaging the T cell receptor influences the nanoscale actin organization and mechanics of the immune synapse. Using an engineered T cell system expressing a specific T cell receptor and stimulated by a range of antigens, we found that the peak force experienced by the T cell receptor during activation was independent of the unbinding kinetics of the stimulating antigen. Conversely, quantification of the actin retrograde flow velocity at the synapse revealed a striking dependence on the antigen unbinding kinetics. These findings suggest that the dynamics of the actin cytoskeleton actively adjusted to normalize the force experienced by the T cell receptor in an antigen-specific manner. Consequently, tuning actin dynamics in response to antigen kinetics may thus be a mechanism that allows T cells to adjust the lengthscale and timescale of T cell receptor signaling.

The Drosophila protein, Nausicaa, regulates lamellipodial actin dynamics in a Cortactin-dependent manner.

ABSTRACTDrosophila CG10915 is an uncharacterized protein coding gene with sequence similarity to human Cortactin-binding protein 2 (CTTNBP2) and Cortactin-binding protein 2 N-terminal-like (CTTNBP2NL). Here, we have named this gene Nausicaa (naus) and characterize it through a combination of quantitative live-cell total internal reflection fluorescence microscopy, electron microscopy, RNAi depletion and genetics. We found that Naus co-localizes with F-actin and Cortactin in the lamellipodia of Drosophila S2R+ and D25c2 cells and this localization is lost following Cortactin or Arp2/3 depletion or by mutations that disrupt a conserved proline patch found in its mammalian homologs. Using permeabilization activated reduction in fluorescence and fluorescence recovery after photobleaching, we find that depletion of Cortactin alters Naus dynamics leading to a decrease in its half-life. Furthermore, we discovered that Naus depletion in S2R+ cells led to a decrease in actin retrograde flow and a lamellipodia characterized by long, unbranched filaments. We demonstrate that these alterations to the dynamics and underlying actin architecture also affect D25c2 cell migration and decrease arborization in Drosophila neurons. We present the hypothesis that Naus functions to slow Cortactin's disassociation from Arp2/3 nucleated branch junctions, thereby increasing both branch nucleation and junction stability.

Model for Coordination of Microtubule and Actin Dynamics in Growth Cone Turning

In the developing nervous system, axons are guided to their synaptic targets by motile structures at the axon tip called growth cones, which reorganize their cytoskeleton in order to steer in response to chemotactic cues. Growth cone motility is mediated by an actin-adhesion “clutch” mechanism, in which mechanical attachment to a substrate, coupled with polarized actin growth, produces leading-edge protrusion. Several studies suggest that dynamic microtubules (MTs) in the growth cone periphery play an essential role in growth cone steering. It is not yet well-understood how the MT cytoskeleton and the dynamic actin-adhesion clutch system are coordinated to promote growth cone navigation. I introduce an experimentally motivated stochastic model of the dynamic reorganization of the growth cone cytoskeleton in response to external guidance cues. According to this model, asymmetric decoupling of MTs from actin retrograde flow leads to a local influx of MTs to the growth cone leading edge, and the leading-edge MT accumulation is amplified by positive feedback between MTs and the actin-adhesion clutch system. Local accumulation of MTs at the leading edge is hypothesized to increase actin adhesion to the substrate, which attenuates actin retrograde flow and promotes leading-edge protrusion. Growth cone alignment with the chemotactic gradient is predicted to be most effective for intermediate levels of sensitivity of the adhesion strength to the presence of leading-edge MTs. Quantitative predictions of the MT distribution and the local rate of retrograde actin flow will allow the hypothetical positive feedback mechanism to be experimentally tested.

Abstract 3154: Harnessing the adaptive potential of mechanoresponsive proteins to overwhelm pancreatic cancer dissemination and invasion

Abstract Metastatic disease is often characterized by altered cellular contractility and deformability, lending cells and groups of cells the flexibility to navigate through different microenvironments. This ability to change cell shape is driven in large part by the structural elements of the mechanobiome, which includes cytoskeletal proteins that sense and respond to mechanical stimuli. Here, we demonstrate that key mechanoresponsive proteins (those that accumulate in response to mechanical stress), specifically nonmuscle myosin IIA and IIC, α- actinin 4, and filamin B, are highly upregulated in pancreatic ductal adenocarcinoma cancer (PDAC) and in patient-derived pancreatic cancer cell lines. Their less responsive sister paralogs (myosin IIB, α-actinin 1, and filamin A) show a smaller dynamic range or disappear with PDAC progression. We demonstrate that these mechanoresponsive proteins directly impact cell mechanics using knockdown and overexpression cell lines. We further quantify the nonmuscle myosin II family members in patient-derived cell lines and identify a role for myosin IIC in the formation of transverse actin arcs in single cells and cortical actin belts in tissue spheroids. We harness the upregulation of myosin IIC and its impact of cytoskeletal architecture through the use of the mechanical modulator 4-hydroxyacetophenone (4-HAP), which increases myosin IIC assembly and stiffens cells. Here, 4-HAP decreases dissemination, induces cortical actin belts, and slows retrograde actin flow in spheroids. Finally, mice having undergone hemisplenectomies with PDAC cells and then treated with 4-HAP have a reduction in liver metastases. Thus, increasing the activity of these mechanoresponsive proteins (in this case, by increasing myosin IIC assembly) to overwhelm the ability of cells to polarize and invade may be an effective strategy to improve the five-year survival rate of pancreatic cancer patients, currently hovering around 6%. Citation Format: Alexandra Surcel, Eric S. Schiffhauer, Dustin G. Thomas, Qingfeng Zhu, Kathleen DiNapoli, Maik Herbig, Oliver Otto, Jochen Guck, Elizabeth Jaffee, Pablo A. Iglesias, Robert A. Anders, Douglas N. Robinson. Harnessing the adaptive potential of mechanoresponsive proteins to overwhelm pancreatic cancer dissemination and invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3154.

Actin Cross-Linking Toxin Is a Universal Inhibitor of Tandem-Organized and Oligomeric G-Actin Binding Proteins

Delivery of bacterial toxins to host cells is hindered by host protective barriers. This obstruction dictates a remarkable efficiency of toxins, a single copy of which may kill a host cell. Efficiency of actin-targeting toxins is further hampered by an overwhelming abundance of their target. The actin cross-linking domain (ACD) toxins of Vibrio species and related bacterial genera catalyze the formation of covalently cross-linked actin oligomers. Recently, we reported that the ACD toxicity can be amplified via a multivalent inhibitory association of actin oligomers with actin assembly factors formins, suggesting that the oligomers may act as secondary toxins. Importantly, many proteins involved in nucleation, elongation, severing, branching, and bundling of actin filaments contain G-actin-binding Wiskott-Aldrich syndrome protein (WASP)-homology motifs 2 (WH2) organized in tandem and therefore may act as a multivalent platform for high-affinity interaction with the ACD-cross-linked actin oligomers. Using live-cell single-molecule speckle (SiMS) microscopy, total internal reflection fluorescence (TIRF) microscopy, and actin polymerization assays, we show that, in addition to formins, the oligomers bind with high affinity and potently inhibit several families of actin assembly factors: Ena/vasodilator-stimulated phosphorprotein (VASP); Spire; and the Arp2/3 complex, both invitro and in live cells. As a result, ACD blocks the actin retrograde flow and membrane dynamics and disrupts association of Ena/VASP with adhesion complexes. This study defines ACD as a universal inhibitor of tandem-organized G-actin binding proteins that overcomes the abundance of actin by redirecting the toxicity cascade toward less abundant targets and thus leading to profound disorganization of the actin cytoskeleton and disruption of actin-dependent cellular functions.

Actin retrograde flow controls natural killer cell response by regulating the conformation state of SHP-1.

Natural killer (NK) cells are a powerful weapon against viral infections and tumor growth. Although the actin-myosin (actomyosin) cytoskeleton is crucial for a variety of cellular processes, the role of mechanotransduction, the conversion of actomyosin mechanical forces into signaling cascades, was never explored in NK cells. Here, we demonstrate that actomyosin retrograde flow (ARF) controls the immune response of primary human NK cells through a novel interaction between β-actin and the SH2-domain-containing protein tyrosine phosphatase-1 (SHP-1), converting its conformation state, and thereby regulating NK cell cytotoxicity. Our results identify ARF as a master regulator of the NK cell immune response. Since actin dynamics occur in multiple cellular processes, this mechanism might also regulate the activity of SHP-1 in additional cellular systems.

Immunology: Is Actin at the Lytic Synapse a Friend or a Foe?

Cytotoxic Tcells and natural killer cells defend us against disease by secreting lytic granules. Whether actin facilitates or thwarts lytic granule secretion has been an open question. Recent results now indicate that the answer depends on the maturation stage of the immune cell-target cell contact.