Amiloride inhibits macropinocytosis by lowering submembranous pH and preventing Rac1 and Cdc42 signaling

Koivusalo, Mirkka; Welch, Christopher; Hayashi, Hideharu; Scott, Cameron C.; Kim, Moshe; Alexander, Todd; Touret, Nicolas; Hahn, Klaus; Grinstein, Sergio

doi:10.1083/jcb.20090808620100331c

Cited by 174 publications

(280 citation statements)

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“…As a clinical inhibitor of the Na ＋ /H ＋ exchanger, EIPA plays an important role in macropinocytosis formation (Koivusalo et al, 2010), and wortmannin is a covalent inhibitor of phosphatidylinositol 3-kinases (PI3K), which is involved in multiple stages of macropinocytosis (Mercer and Helenius, 2012). Therefore, we used EIPA and wortmannin to clarify the role of macropinocytosis and PI3K in PSV entry and infection.…”

Section: Psv Entry Does Not Depend On Macropinocytosis But Requires Pi3kmentioning

confidence: 99%

Porcine sapelovirus enters PK-15 cells via caveolae-dependent endocytosis and requires Rab7 and Rab11

Zhao

Cui

et al. 2019

Virology

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A B S T R A C TTo comprehensively understand the endocytosis of Sapelovirus A (PSV) entry into PK-15 cells, we studied PSV infection in the context of cell perturbations through drug inhibition, siRNA silencing and overexpression of dominant negative (DN) mutants. We showed here that PSV infection of PK-15 cells was unaffected by pretreated with chlorpromazine, EIPA, knockdown of the clathrin heavy chain or overexpression of Eps15 DN mutant. Conversely, PSV infection was sensitive to NH 4 Cl, chloroquine, dynasore, nystatin, MβCD and wortmannin with reduced PSV VP1 expression levels and virus titer. Additionally, PSV invasion leaded to rapid actin rearrangement and disruption of the cellular actin network enhanced PSV infection. After internalization the virus was transported to late endosomes and/or cycling endosomes that requires the participation of Rab7 and Rab11. Our findings demonstrate that PSV uses caveolae-dependent endocytosis as the predominant entry portal into PK-15 cells which requires low pH, dynamin, Rab7 and Rab11.

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Section: Psv Entry Does Not Depend On Macropinocytosis But Requires Pi3kmentioning

confidence: 99%

Porcine sapelovirus enters PK-15 cells via caveolae-dependent endocytosis and requires Rab7 and Rab11

Zhao

Cui

et al. 2019

Virology

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“…Both require phosphoinositide 3-kinase (PI3K) signaling (Araki et al, 1996), phospholipase Cγ (Amyere et al, 2000;Cheeseman et al, 2006), Rac1 (Caron and Hall, 1998;Ridley et al, 1992), and dynamin (Liu et al, 2008;Cao et al, 2007;Gold et al, 1999;Tse et al, 2003), making differentiation between the two processes by targeting components difficult. The only macropinocytosis specific inhibitor, EIPA, functions by deregulating intracellular pH and thus may disrupt additional aspects of the viral life cycle that contribute to inhibition of virus infection (Koivusalo et al, 2010).…”

Section: Uptake Of Apoptotic Bodies By Pveers and Implications For VImentioning

confidence: 99%

Phosphatidylserine receptors: Enhancers of enveloped virus entry and infection

2014

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A variety of both RNA and DNA viruses envelop their capsids in a lipid bilayer. One of the more recently appreciated benefits this envelope is incorporation of phosphatidylserine (PtdSer). Surface exposure of PtdSer disguises viruses as apoptotic bodies; tricking cells into engulfing virions. This mechanism is termed apoptotic mimicry. Several PtdSer receptors have been identified to enhance virus entry and we have termed this group of proteins PtdSer-mediated virus entry enhancing receptors or PVEERs. These receptors enhance entry of a broad range of enveloped viruses. Internalization of virions by PVEERs provides a broad mechanism of entry with little investment by the virus itself and may allow some viruses to attach to cells, thereby making viral glycoprotein/cellular receptor interactions more probable. Alternatively, other viruses may rely entirely on PVEERs for internalization into endosomes. This review provides an overview of PtdSer receptors that serve as PVEERs and the biology behind virion/PVEER interaction.

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“…Two separate groups have shown that HIV-1 replication is reduced in macrophages infected in the presence of amiloride derivatives such as DMA and EIPA (24,25). These drugs specifically inhibit macropinocytosis by acting on Na (ϩ) /H (ϩ) exchange and submembranous pH, thereby affecting F-actin remodeling (36). The authors concluded that macropinocytosis is involved in HIV-1 infection in such cells.…”

Section: Macropinocytosis Is Involved In Hiv-1 Endocytosis In Macrophmentioning

confidence: 99%

Macropinocytosis-Like HIV-1 Internalization in Macrophages Is CCR5 Dependent and Leads to Efficient but Delayed Degradation in Endosomal Compartments

Gobeil

Lodge

Tremblay

2013

J Virol

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HIV-1 endocytosis by a macropinocytosis-like mechanism has been shown to lead to productive infection in macrophages. However, little is known of this pathway. In this study, we examined HIV-1 endocytosis using biochemical approaches and imaging techniques in order to better understand the mechanisms that allow for productive infection of these cells via the endosomal pathway. We show here that this macropinocytosis-like mechanism is not the sole pathway involved in HIV-1 endocytosis in macrophages. However, this pathway specifically requires CCR5 engagement at the cell surface, which in turn suggests that the virus and its coreceptor are present in the endosomal environment simultaneously. Furthermore, although we observed efficient viral degradation following endocytosis, analyses of HIV-1 transport through the endolysosomal pathway revealed that viral degradation is delayed following endosomal internalization, possibly allowing the virus to complete its fusion.

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Amiloride inhibits macropinocytosis by lowering submembranous pH and preventing Rac1 and Cdc42 signaling

Abstract: Figure 2. (B) Top: schematic of the structure of membrane-targeted SEpHluorin/mCherry chimaera used to measure pH sm . Bottom: confocal images of SEpHluorin (left) and mCherry fluorescence (right) in A431 cells. Bar, 10 µm.

Cited by 174 publications

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Porcine sapelovirus enters PK-15 cells via caveolae-dependent endocytosis and requires Rab7 and Rab11

Porcine sapelovirus enters PK-15 cells via caveolae-dependent endocytosis and requires Rab7 and Rab11

Phosphatidylserine receptors: Enhancers of enveloped virus entry and infection

Macropinocytosis-Like HIV-1 Internalization in Macrophages Is CCR5 Dependent and Leads to Efficient but Delayed Degradation in Endosomal Compartments

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