Virus entry by macropinocytosis

Mercer, Jason; Helenius, Ari

doi:10.1038/ncb0509-510

Cited by 738 publications

(976 citation statements)

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“…In summary, we observed that closely related virus particles were capable of eliciting different macropinocytic programs in the same cells. It is known that macropinocytosis can differ between cells (36), but here two distinct responses were observed in the same cells. The plasticity of VACV and its interaction with host cells revealed by our observations demonstrated that the virus is capable of exploiting a repertoire of alternative host-cell responses.…”

Section: Discussionmentioning

confidence: 94%

Vaccinia virus strains use distinct forms of macropinocytosis for host-cell entry

Mercer

Knébel

Schmidt

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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To enter host cells, vaccinia virus, a prototype poxvirus, can induce transient macropinocytosis followed by endocytic internalization and penetration through the limiting membrane of pinosomes by membrane fusion. Although mature virions (MVs) of the Western reserve (WR) strain do this in HeLa cells by activating transient plasma membrane blebbing, MVs from the International Health Department-J strain were found to induce rapid formation (and lengthening) of filopodia. When the signaling pathways underlying these responses were compared, differences were observed at the level of Rho GTPases. Key to the filopodial formation was the virus-induced activation of Cdc42, and for the blebbing response the activation of Rac1. In addition, unlike WR, International Health Department-J MVs did not rely on genistein-sensitive tyrosine kinase and PI(3)K activities. Only WR MVs had membrane fusion activity at low pH. Inhibitor profiling showed that MVs from both strains entered cells by macropinocytosis and that this was induced by virion-exposed phosphatidylserine. Both MVs relied on the activation of epidermal growth factor receptor, on serine/ threonine kinases, protein kinase C, and p21-activated kinase 1. The results showed that different strains of the same virus can elicit dramatically different responses in host cells during entry, and that different macropinocytic mechanisms are possible in the same cell line through subtle differences in the activating ligand.epidermal growth factor receptor | endocytosis | poxvirus | Rho GTPases | virus entry

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Section: Discussionmentioning

confidence: 94%

Vaccinia virus strains use distinct forms of macropinocytosis for host-cell entry

Mercer

Knébel

Schmidt

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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154

159

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“…Recently, a number of viruses have been shown to use MPC, or MPC-like entry pathways for infection (reviewed by Mercer & Helenius, 2009). MPC is especially active in specialized antigen-presenting cells, such as macrophages and DCs.…”

Section: Discussionmentioning

confidence: 99%

Murine norovirus-1 cell entry is mediated through a non-clathrin-, non-caveolae-, dynamin- and cholesterol-dependent pathway

Gerondopoulos

Jackson

Monaghan

et al. 2010

Journal of General Virology

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For many viruses, endocytosis and exposure to the low pH within acidic endosomes is essential for infection. It has previously been reported that feline calicivirus uses clathrin-mediated endocytosis for entry into mammalian cells. Here, we report that infection of RAW264.7 macrophages by the closely related murine norovirus-1 (MNV-1) does not require the clathrin pathway, as infection was not inhibited by expression of dominant-negative Eps15 or by knockdown of the adaptin-2 complex. Further, infection was not inhibited by reagents that raise endosomal pH. RAW264.7 macrophages were shown not to express caveolin, and flotillin depletion did not inhibit infection, suggesting that caveolae and the flotillin pathway are not required for cell entry. However, MNV-1 infection was inhibited by methyl-b-cyclodextrin and the dynamin inhibitor, dynasore. Addition of these drugs to the cells after a period of virus internalization did not inhibit infection, suggesting the involvement of cholesterol-sensitive lipid rafts and dynamin in the entry mechanism. Macropinocytosis (MPC) was shown to be active in RAW264.7 macrophages (as indicated by uptake of dextran) and could be blocked by 5-(N-ethyl-N-isopropyl) amiloride (EIPA), which is reported to inhibit this pathway. However, infection was enhanced in the presence of EIPA. Similarly, actin disruption, which also inhibits MPC, resulted in enhanced infection. These results suggest that MPC could contribute to virus degradation or that inhibition of MPC could lead to the upregulation of other endocytic pathways of virus uptake. INTRODUCTIONThe family Caliciviridae is divided into four genera: Vesivirus, Lagovirus, Sapovirus and Norovirus. The human noroviruses are the most common cause of acute viral gastroenteritis, especially in industrialized countries (Lopman et al., 2003); there is currently no treatment or vaccine for these viruses. In addition, there is still no routine tissue culture system for the propagation of human noroviruses, but the recent discovery of murine norovirus-1 (MNV-1) has provided an efficient model system for the study of norovirus replication, as this virus replicates efficiently in murine macrophages and dendritic cells (DCs) (Karst et al., 2003;Wobus et al., 2004). MNV-1 is highly prevalent in laboratory mice and has been shown to be lethal to mice with impaired innate immunity (Hsu et al., 2006;Karst et al., 2003;Muller et al., 2007).Noroviruses are non-enveloped and contain a singlestranded RNA genome of about 7.3 kb, which is linked to the viral VPg protein at the 59 end and is polyadenylated at the 39 end (Karst et al., 2003;Wobus et al., 2004). The genome is organized into four open reading frames (ORF-1-4). ORF-1 encodes the non-structural proteins, whereas ORF-2 and ORF-3 encode structural proteins (Sosnovtsev et al., 2006). ORF-4 was recently identified within the MNV-1 genome and encodes a single protein of unknown function (Thackray et al., 2007).For many viruses, infection requires virus uptake by endocytosis. A number of different endo...

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“…Macropinocytosis is a triggered process involving complex signaling and vigorous, cell‐wide actin ruffling leading to plasma membrane protrusions. The ruffles can take the form of circular projections, lamellipodia and blebs 15. Macropinosomes are large, fluid‐filled, cytoplasmic vacuoles formed by membrane fission when the protrusions collapse back onto the plasma membrane 16.…”

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confidence: 99%

“…To date, over 20 different viruses from diverse families have been shown to use macropinocytosis for infectious entry (reviewed in 15 31). Amongst these is vaccinia virus (VACV), a large, enveloped, dsDNA virus characterized by its structural complexity and cytoplasmic life cycle.…”

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confidence: 99%

Vaccinia Virus Infection Requires Maturation of Macropinosomes

Rizopoulos

Balistreri

Kilcher

et al. 2015

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The prototypic poxvirus, vaccinia virus (VACV), occurs in two infectious forms, mature virions (MVs) and extracellular virions (EVs). Both enter HeLa cells by inducing macropinocytic uptake. Using confocal microscopy, live‐cell imaging, targeted RNAi screening and perturbants of endosome maturation, we analyzed the properties and maturation pathway of the macropinocytic vacuoles containing VACV MVs in HeLa cells. The vacuoles first acquired markers of early endosomes [Rab5, early endosome antigen 1 and phosphatidylinositol(3)P]. Prior to release of virus cores into the cytoplasm, they contained markers of late endosomes and lysosomes (Rab7a, lysosome‐associated membrane protein 1 and sorting nexin 3). RNAi screening of endocytic cell factors emphasized the importance of late compartments for VACV infection. Follow‐up perturbation analysis showed that infection required Rab7a and PIKfyve, confirming that VACV is a late‐penetrating virus dependent on macropinosome maturation. VACV EV infection was inhibited by depletion of many of the same factors, indicating that both infectious particle forms share the need for late vacuolar conditions for penetration.

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Virus entry by macropinocytosis

Cited by 738 publications

References 125 publications

Vaccinia virus strains use distinct forms of macropinocytosis for host-cell entry

Vaccinia virus strains use distinct forms of macropinocytosis for host-cell entry

Murine norovirus-1 cell entry is mediated through a non-clathrin-, non-caveolae-, dynamin- and cholesterol-dependent pathway

Vaccinia Virus Infection Requires Maturation of Macropinosomes

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