A<i>Diaphanous</i>-related formin links Ras signaling directly to actin assembly in macropinocytosis and phagocytosis

Junemann, Alexander; Filić, Vedrana; Winterhoff, Moritz; Nordholz, Benjamin; Litschko, Christof; Schwellenbach, Helena; Stephan, Till; Weber, Igor; Faix, Jan

doi:10.1073/pnas.1611024113

Cited by 71 publications

(115 citation statements)

References 84 publications

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“…One possibility is that SCAR and Arp2/3 are preferentially recruited by newly synthesised F-actin (Ichetovkin et al, 2002) produced by formins (Jasnin et al, 2016), which might therefore be the initial actin nucleator to be recruited. However, this seems unlikely in the light of recent work showing that ForG contributes to the base of the macropinocytic cup, but seemingly not to the extending lip (Junemann et al, 2016). Alternatively, SCAR might be moved to the periphery of Ras/PIP 3 patches, perhaps by myosin-1 motors.…”

Section: Discussionmentioning

confidence: 97%

“…The dynamic actin that polymerises around macropinocytic cups is probably initiated by a number of nucleators, including both formins, such as ForG, which is needed for the basal part of phagocytic cups in Dictyostelium (Junemann et al, 2016), and the Arp2/3 complex (Insall et al, 2001), which produces dendritic structures (Pollard and Borisy, 2003), like the actin that drives pseudopods. Assembly of Arp2/3 based actin is controlled by the WASP family of nucleation promoting factors; the two family members that act at the plasma membrane are WASP and SCAR/WAVE (hereafter called SCAR).…”

Section: Introductionmentioning

confidence: 99%

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A plasma membrane template for macropinocytic cups

Veltman

Williams

Bloomfield

et al. 2016

eLife

158

253

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Macropinocytosis is a fundamental mechanism that allows cells to take up extracellular liquid into large vesicles. It critically depends on the formation of a ring of protrusive actin beneath the plasma membrane, which develops into the macropinocytic cup. We show that macropinocytic cups in Dictyostelium are organised around coincident intense patches of PIP3, active Ras and active Rac. These signalling patches are invariably associated with a ring of active SCAR/WAVE at their periphery, as are all examined structures based on PIP3 patches, including phagocytic cups and basal waves. Patch formation does not depend on the enclosing F-actin ring, and patches become enlarged when the RasGAP NF1 is mutated, showing that Ras plays an instructive role. New macropinocytic cups predominantly form by splitting from existing ones. We propose that cup-shaped plasma membrane structures form from self-organizing patches of active Ras/PIP3, which recruit a ring of actin nucleators to their periphery.DOI: http://dx.doi.org/10.7554/eLife.20085.001

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

A plasma membrane template for macropinocytic cups

Veltman

Williams

Bloomfield

et al. 2016

eLife

158

253

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“…Formins have been demonstrated to play important role in actin polymerisation during phagocytosis in mammalian and other systems (Junemann et al, 2016;Naj, Hoffmann, Himmel, & Linder, 2013;Rengarajan, Hayer, & Theriot, 2016). In particular, mDia interacts directly with both RhoA and profilin and is recruited to phagocytic sites, suggesting that RhoA co-ordinately regulates site-specific actin polymerisation through formin and profilin (Salinas et al, 2015).…”

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confidence: 99%

EhRho1 regulates phagocytosis by modulating actin dynamics through EhFormin1 and EhProfilin1 inEntamoeba histolytica

Bharadwaj

Sharma

Arya

et al. 2018

Cellular Microbiology

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The protist parasite Entamoeba histolytica causes amoebiasis, a major public health problem in developing countries and a major cause of morbidity and mortality. Invasive infection in amoebiasis mostly affects intestinal epithelial cell lining but can also involve other organs, such as liver, lungs, or brain. Phagocytosis is an essential mode of nutrition in amoeba and has often been associated with virulence behaviour of E. histolytica. E. histolytica possesses a highly dynamic and actin-rich cytoskeleton that is thought to be involved in many processes, such as motility, pseudopod formation, and pathogenesis. Rho GTPases are known to be key regulators of the actin cytoskeleton and consequently influence the shape and movement of cells. Our study is mainly focused to understand the role of EhRho1 in the phagocytosis process of E. histolytica. EhRho1 got enriched in the phagocytic cups along with EhActin and remains attached with phagosomal membrane. However, there was no direct binding of EhRho1 with G- or F-actin, though binding was observed with the actin nucleating proteins EhFormin1 and EhProfilin1. Overexpression of dominant negative mutant or lowering the expression by antisense RNA of EhRho1 in trophozoites caused delocalisation of EhFormin1 and EhProfilin1 from phagocytic cups, which results in impairment of phagocytic process and decrease in F-actin content. The overall results show that EhRho1 regulates phagocytosis by modulating actin dynamics through recruitment of EhFormin1 and EhProfilin1 at the phagocytosis nucleation site in E. histolytica.

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“…Dictyostelium has a plethora of Ras genes but the key Ras proteins for macropinocytosis appear to be RasG and RasS , Bolourani et al, 2006, Williams et al, 2019a. However, a double mutant still takes up fluid at about 35% of the parental rate, indicating that at least one more Ras protein is involved, which is likely RasB (Junemann et al, 2016).…”

Section: Upstream Of Pip3: Ras and Its Regulatorsmentioning

confidence: 99%

Living on soup: macropinocytic feeding in amoebae

Kay¹,

Williams²,

Manton³

et al. 2019

Int. J. Dev. Biol.

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Macropinocytosis is used by a variety of amoebae for feeding on liquid medium. The amoebae project cups and ruffles from their plasma membrane, driven by actin polymerization, and eventually fuse these back to the membrane, entrapping droplets of medium into internal vesicles. These vesicles are of up to several microns in diameter and are processed through the lysosomal digestive system to extract nutrients. Recognizably the same process is used in metazoan cells for a number of medically important purposes, including the pathological growth of cancer cells. We describe the discovery of macropinocytosis in Dictyostelium amoebae, its genetic regulation by the NF1 RasGAP, and the tools available for its investigation. Work on Dictyostelium over the last 30 years has identified many genes that may be important for macropinocytosis, which are listed at dictyBase, and give a basis for mechanistic studies. We argue that the actin cytoskeleton is organized for macropinocytosis by a signalling patch of PIP3 and active Ras and Rac, together with their regulatory proteins and effectors, including the protein kinases Akt and SGK. The Scar/ WAVE complex is recruited to the periphery of this patch, triggering the formation of a hollow ring of protrusive actin polymerization, and eventually a macropinocytic cup. Major problems to be addressed include: the dynamics sustaining macropinocytic patches and the mechanism of Scar/WAVE recruitment; the mechanisms of cup closure and of membrane fusion; the ecological situations where amoebae feed by macropinocytosis; and the evolutionary relationship between macropinocytosis and growth factor signalling.

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ADiaphanous-related formin links Ras signaling directly to actin assembly in macropinocytosis and phagocytosis

Cited by 71 publications

References 84 publications

A plasma membrane template for macropinocytic cups

A plasma membrane template for macropinocytic cups

EhRho1 regulates phagocytosis by modulating actin dynamics through EhFormin1 and EhProfilin1 inEntamoeba histolytica

Living on soup: macropinocytic feeding in amoebae

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