Kaposi's Sarcoma-Associated Herpesvirus Utilizes an Actin Polymerization-Dependent Macropinocytic Pathway To Enter Human Dermal Microvascular Endothelial and Human Umbilical Vein Endothelial Cells

Raghu, Hari; Sharma-Walia, Neelam; Veettil, Mohanan Valiya; Sadagopan, Sathish; Chandran, Bala

doi:10.1128/jvi.02498-08

Cited by 131 publications

(203 citation statements)

References 70 publications

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“…Further- more, c-Cbl and myosin-IIA are known regulators of KSHV macropinocytosis and their complex formation with EphA2 strongly advocates for a critical role of EphA2 during macropinocytosis. This outcome is supported by previous studies where c-Cbl mediated internalization of EphA2 (30). Although, c-Cbl drives the KSHV-receptor translocations into LRs, abrogation of sustained activation of c-Cbl and myosin-IIA and KSHV translocations by EphA2 shRNA clearly suggest that EphA2 augments c-Cbl-driven mechanisms in LRs and acts as a critical regulator of macropinocytosis.…”

Section: Discussionsupporting

confidence: 74%

“…Although microtubules and Rho-GTPases are known to regulate KSHV trafficking and entry (30), the current study reveals the dependency of Rho-GTPase on the upstream membrane protein EphA2 (7,46). EphA2 also appears to be essential for Rab5 association with internalized KSHV in the early macropinosome and productive trafficking of KSHV.…”

Section: Discussionmentioning

confidence: 84%

“…Our studies above demonstrated that knocking down EphA2 reduced KSHV-induced signaling, virus entry, and viral gene expression. KSHV-induced signaling is highly coupled to its endocytosis and our previous studies have demonstrated that KSHV enters HMVEC-d cells via macropinocytosis (11,30). Evidence of associations with c-Cbl, myosin IIA, and regulation of KSHV-induced signaling prompted us to examine EphA2's role in macropinocytosis of KSHV.…”

Section: Epha2 Regulates Productive Macropinocytosis Of Kshv In Hmvec-dmentioning

confidence: 99%

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Kaposi’s sarcoma-associated herpesvirus interacts with EphrinA2 receptor to amplify signaling essential for productive infection

Chakraborty

Veettil

Bottero

et al. 2012

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

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157

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Kaposi's sarcoma-associated herpesvirus (KSHV), etiologically associated with Kaposi's sarcoma, uses integrins (α3β1, αVβ3, and αVβ5) and associated signaling to enter human dermal microvascular endothelial cells (HMVEC-d), an in vivo target of infection. KSHV infection activated c-Cbl, which induced the selective translocation of KSHV into lipid rafts (LRs) along with the α3β1, αVβ3, and xCT receptors, but not αVβ5. LR-translocated receptors were monoubiquitinated, leading to productive macropinocytic entry, whereas non-LR-associated αVβ5 was polyubiquitinated, leading to clathrin-mediated entry that was targeted to lysosomes. Because the molecule(s) that integrate signal pathways and productive KSHV macropinocytosis were unknown, we immunoprecipitated KSHV-infected LR fractions with anti-α3β1 antibodies and analyzed them by mass spectrometry. The tyrosine kinase EphrinA2 (EphA2), implicated in many cancers, was identified in this analysis. EphA2 was activated by KSHV. EphA2 was also associated with KSHV and integrins (α3β1 and αVβ3) in LRs early during infection. Preincubation of virus with soluble EphA2, knockdown of EphA2 by shRNAs, or pretreatment of cells with anti-EphA2 monoclonal antibodies or tyrosine kinase inhibitor dasatinib significantly reduced KSHV entry and gene expression. EphA2 associates with c-Cbl-myosin IIA and augmented KSHV-induced Src and PI3-K signals in LRs, leading to bleb formation and macropinocytosis of KSHV. EphA2 shRNA ablated macropinocytosis-associated signaling events, virus internalization, and productive nuclear trafficking of KSHV DNA. Taken together, these studies demonstrate that the EphA2 receptor acts as a master assembly regulator of KSHV-induced signal molecules and KSHV entry in endothelial cells and suggest that the EphA2 receptor is an attractive target for controlling KSHV infection.virus entry | productive endocytosis | receptor tyrosine kinase

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 84%

Section: Epha2 Regulates Productive Macropinocytosis Of Kshv In Hmvec-dmentioning

confidence: 99%

See 1 more Smart Citation

Kaposi’s sarcoma-associated herpesvirus interacts with EphrinA2 receptor to amplify signaling essential for productive infection

Chakraborty

Veettil

Bottero

et al. 2012

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

Self Cite

157

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“…However, in some cases, scrutiny reveals that caveolae are not the dominant mode of entry, which becomes clear only in cells devoid of caveolae (16). Another mode of virus entry is by constitutive or induced macropinocytosis (17)(18)(19)(20)(21)(22)(23)(24), which can occur through several distinct mechanisms (lamellipodial and circular ruffles as well as filopodial and blebbing macropinocytosis [8,24]). All mechanisms rely on small GTPases of the Rho family and actin remodeling to promote formation of cell surface extrusions, which, when falling back onto the cell, entrap a large volume of extracellular fluid to generate a macropinosome from a few hundred nm up to 10 m in size (8,24).…”

mentioning

confidence: 99%

Macropinocytosis Is the Entry Mechanism of Amphotropic Murine Leukemia Virus

Rasmussen

Vilhardt

2015

J Virol

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The entry mechanism of murine amphotropic retrovirus (A-MLV) has not been unambiguously determined. We show here that A-MLV is internalized not by caveolae or other pinocytic mechanisms but by macropinocytosis. Thus, A-MLV infection of mouse embryonic fibroblasts deficient for caveolin or dynamin, and NIH 3T3 cells knocked down for caveolin expression, was unaffected. Conversely, A-MLV infection of NIH 3T3 and HeLa cells was sensitive to amiloride analogues and actin-depolymerizing drugs that interfere with macropinocytosis. Further manipulation of the actin cytoskeleton through conditional expression of dominant positive or negative mutants of Rac1, PAK1, and RhoG, to increase or decrease macropinocytosis, similarly correlated with an augmented or inhibited infection with A-MLV, respectively. The same experimental perturbations affected the infection of viruses that use clathrin-coated-pit endocytosis or other pathways for entry only mildly or not at all. These data agree with immunofluorescence studies and cryo-immunogold labeling for electron microscopy, which demonstrate the presence of A-MLV in protrusion-rich areas of the cell surface and in cortical fluid phase (dextran)-filled macropinosomes, which also account for up to a half of the cellular uptake of the cell surface-binding lectin concanavalin A. We conclude that A-MLV use macropinocytosis as the predominant entry portal into cells. (1, 2). Although initial attachment of virions to the cell surface might be mediated through other factors, including glycosaminglycans (3) or fibronectin (4), Pit2 is required for entry of the virus and infection (1, 2). Pit2 is a conserved membrane protein with five presumed extracellular loops, of which the first loop forms the binding site for A-Env (1). Pit2 is distributed between the cell surface and intracellular stores (5), and upon A-MLV infection, Pit2 is downregulated from the cell surface and localized to an uncharacterized membrane compartment. The known ability of cells to increase their capacity for phosphate influx when deprived of phosphate in the medium may reside not in changes in Pit2 distribution but rather in posttranslational modification of surface-resident Pit2 transporters (6). IMPORTANCE Binding and entry of virus particles into mammalian cells are the first steps of infection. Understanding how pathogens and toxins exploit or divert endocytosis pathways has advanced our understanding of membrane trafficking pathways, which benefits development of new therapeutic schemes and methods of drug delivery. We show here that amphotropic murine leukemia virus (A-MLVViruses have evolved to utilize practically every known mechanism of endocytosis for cellular entry, including clathrin-coatedpit endocytosis, clathrin-independent internalization pathways, including caveolae and non-caveolin-dependent pathways, and macropinocytosis (7-9). Caveolae are small (50-to 60-nm) omega-shaped invaginations of the plasma membrane carrying a coat structure of caveolin-1 (and -2). They are essentially stable an...

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“…However, the viruses like parvoviruses required further traffic to lysosomes [33]. Some viruses might involve in more than two endocytosis pathways [34][35][36]. e varicella-zoster virion (VSV) does not only trigger clathrin-mediated endocytosis but also required the cholesterol, the component of lipid ra [37].…”

Section: Clathrin-dependent Endocytosismentioning

confidence: 99%

Molecular Signaling and Cellular Pathways for Virus Entry

Chi

Liu

2013

ISRN Virology

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The cell signaling plays a pivotal role in regulating cellular processes and is often manipulated by viruses as they rely on the functions offered by cells for their propagation. The first stage of their host life is to pass the genetic materials into the cell. Although some viruses can directly penetrate into cytosol, in fact, most virus entry into their host cells is through endocytosis. This machinery initiates with cell type specific cellular signaling pathways, and the signaling compounds can be proteins, lipids, and carbohydrates. The activation can be triggered in a very short time after virus binds on target cells, such as receptors. The signaling pathways involved in regulation of viral entry are wide diversity that often cross-talk between different endocytosis results. Furthermore, some viruses have the ability to use the multiple internalization pathways which leads to the regulation being even more complex. In this paper, we discuss some recent advances in our understanding of cellular pathways for virus entry, molecular signaling during virus entry, formation of endocytic vesicles, and the traffic.

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Kaposi's Sarcoma-Associated Herpesvirus Utilizes an Actin Polymerization-Dependent Macropinocytic Pathway To Enter Human Dermal Microvascular Endothelial and Human Umbilical Vein Endothelial Cells

Cited by 131 publications

References 70 publications

Kaposi’s sarcoma-associated herpesvirus interacts with EphrinA2 receptor to amplify signaling essential for productive infection

Kaposi’s sarcoma-associated herpesvirus interacts with EphrinA2 receptor to amplify signaling essential for productive infection

Macropinocytosis Is the Entry Mechanism of Amphotropic Murine Leukemia Virus

Molecular Signaling and Cellular Pathways for Virus Entry

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