Coordinated Ras and Rac Activity Shapes Macropinocytic Cups and Enables Phagocytosis of Geometrically Diverse Bacteria

Buckley, Catherine M.; Pots, Henderikus; Gueho, Aurélie; Vines, James H; Munn, Christopher J.; Phillips, Ben A.; Gilsbach, Bernd; Traynor, David; Nikolaev, Anton; Soldati, Thierry; Parnell, Andrew J.; Kortholt, Arjan; King, Jason

doi:10.1016/j.cub.2020.05.049

Cited by 41 publications

(48 citation statements)

References 69 publications

(100 reference statements)

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“…Evidence suggests that phagocytosis of differently shaped particles requires different signaling cascades. Experiments with the amoeba Dictyostelium showed that the coordinated activity of the small-GTPases Rac and Ras at the phagocytic cup by the multidomain protein RGBARG (RCC1, RhoGEF, BAR, and RasGAP-containing protein) is key for uptake of particles and microbes of different shapes ( 87 ). The authors propose that RGBARG promotes the protrusion of the cytoskeleton at the periphery of the phagocytic cup by expanding Rac activation in this region, while it suppresses Ras at more central regions of the nascent phagocytic cup ( 87 ).…”

Section: Model Particle Size and Shape: Experimental Evidencementioning

confidence: 99%

“…Experiments with the amoeba Dictyostelium showed that the coordinated activity of the small-GTPases Rac and Ras at the phagocytic cup by the multidomain protein RGBARG (RCC1, RhoGEF, BAR, and RasGAP-containing protein) is key for uptake of particles and microbes of different shapes ( 87 ). The authors propose that RGBARG promotes the protrusion of the cytoskeleton at the periphery of the phagocytic cup by expanding Rac activation in this region, while it suppresses Ras at more central regions of the nascent phagocytic cup ( 87 ). Although Dictyostelium without RGBARG showed improved phagocytosis of larger model particles and yeast, the spatial regulation of Ras by RGBARG was found to be important for phagocytosis of elongated cargoes ( 87 ).…”

Section: Model Particle Size and Shape: Experimental Evidencementioning

confidence: 99%

“…The authors propose that RGBARG promotes the protrusion of the cytoskeleton at the periphery of the phagocytic cup by expanding Rac activation in this region, while it suppresses Ras at more central regions of the nascent phagocytic cup ( 87 ). Although Dictyostelium without RGBARG showed improved phagocytosis of larger model particles and yeast, the spatial regulation of Ras by RGBARG was found to be important for phagocytosis of elongated cargoes ( 87 ).…”

Section: Model Particle Size and Shape: Experimental Evidencementioning

confidence: 99%

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Modulation of Immune Responses by Particle Size and Shape

et al. 2021

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The immune system has to cope with a wide range of irregularly shaped pathogens that can actively move (e.g., by flagella) and also dynamically remodel their shape (e.g., transition from yeast-shaped to hyphal fungi). The goal of this review is to draw general conclusions of how the size and geometry of a pathogen affect its uptake and processing by phagocytes of the immune system. We compared both theoretical and experimental studies with different cells, model particles, and pathogenic microbes (particularly fungi) showing that particle size, shape, rigidity, and surface roughness are important parameters for cellular uptake and subsequent immune responses, particularly inflammasome activation and T cell activation. Understanding how the physical properties of particles affect immune responses can aid the design of better vaccines.

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Section: Model Particle Size and Shape: Experimental Evidencementioning

confidence: 99%

Section: Model Particle Size and Shape: Experimental Evidencementioning

confidence: 99%

Section: Model Particle Size and Shape: Experimental Evidencementioning

confidence: 99%

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Modulation of Immune Responses by Particle Size and Shape

et al. 2021

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“…Finally, CARMIL-GAP’s GAP activity may contribute to phagocytosis and chemotactic streaming by regulating additional down-stream effectors of Rac1 (e.g. PAK kinases, formins, IQGAP; (Buckley et al, 2020; Rivero and Xiong, 2016)).…”

Section: Dicussionmentioning

confidence: 99%

Dual regulation of the actin cytoskeleton by CARMIL-GAP

Jung

Pan

Alexander

et al. 2021

Preprint

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CARMIL (Capping protein Arp2/3 Myosin I Linker) proteins are multi-domain scaffold proteins that regulate actin dynamics by regulating the activity of Capping Protein (CP). Here we characterize CARMIL-GAP, a Dictyostelium CARMIL isoform that contains a ~130 residue insert that, by homology, is a GTPase activating (GAP) domain for Rho-related GTPases. Consistently, this GAP domain binds Dictyostelium Rac1a and accelerates its rate of GTP hydrolysis. CARMIL-GAP concentrates with F-actin in phagocytic cups and at the leading edge of chemotaxing cells, and cells devoid of CARMIL-GAP exhibit pronounced defects in phagocytosis and chemotactic streaming. Importantly, these defects are fully rescued by the re-expression of CARMIL-GAP. Finally, the rescue of CARMIL-GAP null cells with versions of CARMIL-GAP that lack either GAP activity or the ability to regulate CP show that while both activities contribute significantly to CARMIL-GAP function, the GAP activity plays the bigger role. Together, our results add to the growing evidence that CARMIL proteins influence actin dynamics by regulating signaling molecules as well as CP, and that the continuous cycling of Rho GTPases between their GTP and GDP bound states is often required to drive Rho-dependent biological processes.

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“…Macropinocytosis is dependent on cytoskeletal remodeling at the plasma membrane to induce the formation of structures called dorsal ruffles that form the beginning of a macropinosome. Ras signaling cascades lead to activation of the Rho GTPase Rac1, initiating actin polymerization and formation of branched actin networks that provide structure for remodeling of the plasma membrane (Swanson, 2008;Fujii et al, 2013;Buckley et al, 2020). One family of proteins important for stabilizing branched actin networks are the α-actinin proteins, which are actin bundling proteins that stabilize the actin cytoskeleton in structures like lamellipodia and focal adhesions (Sjoblom et al, 2008;Murphy and Young, 2015).…”

Section: Introductionmentioning

confidence: 99%

Distinct forms of the actin cross-linking protein α-actinin support macropinosome internalization and trafficking

Burton

Johnson

Krueger

et al. 2021

MBoC

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The α-actinin family of actin cross-linking proteins have been implicated in driving tumor cell metastasis through regulation of the actin cytoskeleton; however, there has been little investigation into whether these proteins can influence tumor cell growth. We demonstrate that α-actinin 1 and 4 are essential for nutrient uptake through the process of macropinocytosis in pancreatic ductal adenocarcinoma (PDAC) cells, and inhibition of these proteins decreases tumor cell survival in the presence of extracellular protein. The α-actinin proteins play essential roles throughout the macropinocytic process, where α-actinin 4 stabilizes the actin cytoskeleton on the plasma membrane to drive membrane ruffling and macropinosome internalization, and α-actinin 1 localizes to actin tails on macropinosomes to facilitate trafficking to the lysosome for degradation. In addition to tumor cell growth, we also observe that the α-actinin proteins can influence uptake of chemotherapeutics and extracellular matrix (ECM) proteins through macropinocytosis, suggesting that the α-actinin proteins can regulate multiple tumor cell properties through this endocytic process. In summary, these data demonstrate a critical role for the α-actinin isoforms in tumor cell macropinocytosis, thereby affecting growth and invasive potential of PDAC tumors. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text]

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Coordinated Ras and Rac Activity Shapes Macropinocytic Cups and Enables Phagocytosis of Geometrically Diverse Bacteria

Cited by 41 publications

References 69 publications

Modulation of Immune Responses by Particle Size and Shape

Modulation of Immune Responses by Particle Size and Shape

Dual regulation of the actin cytoskeleton by CARMIL-GAP

Distinct forms of the actin cross-linking protein α-actinin support macropinosome internalization and trafficking

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