Virus entry at a glance

Yamauchi, Yohei; Helenius, Ari

doi:10.1242/jcs.119685

Cited by 213 publications

(199 citation statements)

References 146 publications

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“…A hallmark of virus entry by macropinocytosis is activation of signaling pathways following virus attachment and receptor clustering (11,42,51). These pathways are necessary for initiating actin remodeling that ensures membrane ruffling, invagination, and maturation of macropinosomes and primes host cells for infection (56). Inhibitors targeting different steps in the macropinosome formation process have been used to elucidate the mechanisms of virus entry.…”

Section: Resultsmentioning

confidence: 99%

Cell Surface THY-1 Contributes to Human Cytomegalovirus Entry via a Macropinocytosis-Like Process

Fischer

Cohen

2016

J Virol

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Previously we showed that THY-1 has a critical role in the initial stage of infection of certain cell types with human cytomegalovirus (HCMV) and that THY-1 is important for HCMV-mediated activation of phosphatidylinositol 3-kinase (PI3K)/Akt during virus entry. THY-1 is known to interact with integrins and is a major cargo protein of clathrin-independent endocytic vesicles. Since macropinocytosis involves integrin signaling, is PI3K/Akt dependent, and is a clathrin-independent endocytic process, we determined whether THY-1 has a role in HCMV entry by macropinocytosis. Using electron microscopy in two cell lines that support HCMV infection in a THY-1-dependent manner, we found that HCMV enters these cells by a macropinocytosis-like process. THY-1 associated with HCMV virions on the cell surface and colocalized with virus inside macropinosomes. 5-(N-Ethyl-Nisopropyl)amiloride (EIPA) and soluble THY-1 blocked HCMV infection in the cell lines by >80% and 60%, respectively. HCMV entry into the cells triggered increased influx of extracellular fluid, a marker of macropinocytosis, and this increased fluid uptake was inhibited by EIPA and by soluble THY-1. Blocking actin depolymerization, Na ؉ /H ؉ exchange, PI3K, and Pak1 kinase, which are critical for macropinocytosis, impaired HCMV infection. Neither internalized HCMV virions nor THY-1 in virus-infected cells colocalized with transferrin as determined by confocal microscopy, indicating that clathrin-mediated endocytosis was not involved in THY-1-associated virus entry. These results suggest that HCMV has adapted to utilize THY-1, a cargo protein of clathrin-independent endocytotic vesicles, to facilitate efficient entry into certain cell types by a macropinocytosis-like process. IMPORTANCE Human cytomegalovirus (HCMV) infects over half of the population and is the most common infectious cause of birth defects.The virus is the most important infection occurring in transplant recipients. The mechanism of how HCMV enters cells is controversial. In this study, we show that THY-1, a cell surface protein that is critical for the early stage of entry of HCMV into certain cell types, contributes to virus entry by macropinocytosis. Our findings suggest that HCMV has adapted to utilize THY-1 to facilitate entry of HCMV into macropinosomes in certain cell types. Further knowledge about the mechanism of HCMV entry into cells may facilitate the development of novel inhibitors of virus infection. Human cytomegalovirus (HCMV) infects over half of the general population. While the infection is often asymptomatic when occurring in young children, it poses a serious health threat in transplant recipients and in immunocompromised individuals. HCMV is the most common infectious cause of birth defects. The virus infects a variety of host cells in vivo, including epithelial, endothelial, and muscle cells as well as fibroblasts. HCMV encodes multiple glycoproteins, some of which are not shared with other human herpesviruses, such as UL128, UL130, and UL131A. Other glycoproteins ar...

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Section: Resultsmentioning

confidence: 99%

Cell Surface THY-1 Contributes to Human Cytomegalovirus Entry via a Macropinocytosis-Like Process

Fischer

Cohen

2016

J Virol

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“…Next, we investigated the roles of Pak1, PKC, TKs, EGFR, and CtBP1, which are often required for macropinocytosis (5,6,57,70). While HSV-1 gene expression was strongly reduced , triplicates) measured in Vero (n ϭ 7), HeLaS3 (n ϭ 9), HEp-2 (n ϭ 5), or PtK 2 (n ϭ 5) cells and cell viability (gray bars, trypan blue, mean Ϯ SD, n ϭ 2 in triplicates) were normalized to 100% for DMSO-treated cells.…”

Section: Resultsmentioning

confidence: 99%

Herpes Simplex Virus Internalization into Epithelial Cells Requires Na ⁺ /H ⁺ Exchangers and p21-Activated Kinases but neither Clathrin- nor Caveolin-Mediated Endocytosis

Devadas

Koithan

Diestel

et al. 2014

J Virol

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Herpes simplex virus 1 (HSV-1) is an alphaherpesvirus that has been reported to infect some epithelial cell types by fusion at the plasma membrane but others by endocytosis. To determine the molecular mechanisms of productive HSV-1 cell entry, we perturbed key endocytosis host factors using specific inhibitors, RNA interference (RNAi), or overexpression of dominant negative proteins and investigated their effects on HSV-1 infection in the permissive epithelial cell lines Vero, HeLa, HEp-2, and PtK 2 . HSV-1 internalization required neither endosomal acidification nor clathrin-or caveolin-mediated endocytosis. In contrast, HSV-1 gene expression and internalization were significantly reduced after treatment with 5-(N-ethyl-N-isopropyl)amiloride (EIPA). EIPA blocks the activity of Na ؉ /H ؉ exchangers, which are plasma membrane proteins implicated in all forms of macropinocytosis. HSV-1 internalization furthermore required the function of p21-activated kinases that contribute to macropinosome formation. However, in contrast to some forms of macropinocytosis, HSV-1 did not enlist the activities of protein kinase C (PKC), tyrosine kinases, C-terminal binding protein 1, or dynamin to activate its internalization. These data suggest that HSV-1 depends on Na ؉ /H ؉ exchangers and p21-activated kinases either for macropinocytosis or for local actin rearrangements required for fusion at the plasma membrane or subsequent passage through the actin cortex underneath the plasma membrane. IMPORTANCE After initial replication in epithelial cells, herpes simplex viruses (HSVs) establish latent infections in neurons innervating these regions.Upon primary infection and reactivation from latency, HSVs cause many human skin and neurological diseases, particularly in immunocompromised hosts, despite the availability of effective antiviral drugs. Many viruses use macropinocytosis for virus internalization, and many host factors mediating this entry route have been identified, although the specific perturbation profiles vary for different host and viral cargo. In addition to an established entry pathway via acidic endosomes, we show here that HSV-1 internalization depended on sodium-proton exchangers at the plasma membrane and p21-activated kinases. These results suggest that HSV-1 requires a reorganization of the cortical actin cytoskeleton, either for productive cell entry via pHindependent fusion from macropinosomes or for fusion at the plasma membrane, and subsequent cytosolic passage to microtubules that mediate capsid transport to the nucleus for genome uncoating and replication.

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“…In comparison to EVs, viruses also use various receptors for their multistep attachment and cellular entry process and often induce changes on the target plasma membrane, activating signaling pathways (74). Selectivity of EV binding may also be reliant on exogenous cues.…”

Section: Virus Attachment Molecules Are Exposed On the Ev Surfacementioning

confidence: 99%

“…The envelopes of these viruses consist of host membrane lipids, sterols, and proteins. Fusion with the plasma membrane is mediated by virus-encoded glycoproteins (74,87) and fusogenic host factors that include tetraspanins. The first step to membrane fusion is tethering or attachment, as described above.…”

Section: Mechanism Of Viral Fusion With the Plasma Membrane Direct Fumentioning

confidence: 99%

Extracellular Vesicles Exploit Viral Entry Routes for Cargo Delivery

Dongen

Masoumi

Witwer

et al. 2016

Microbiol Mol Biol Rev

232

193

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SUMMARYExtracellular vesicles (EVs) have emerged as crucial mediators of intercellular communication, being involved in a wide array of key biological processes. Eukaryotic cells, and also bacteria, actively release heterogeneous subtypes of EVs into the extracellular space, where their contents reflect their (sub)cellular origin and the physiologic state of the parent cell. Within the past 20 years, presumed subtypes of EVs have been given a rather confusing diversity of names, including exosomes, microvesicles, ectosomes, microparticles, virosomes, virus-like particles, and oncosomes, and these names are variously defined by biogenesis, physical characteristics, or function. The latter category, functions, in particular the transmission of biological signals between cellsin vivoand how EVs control biological processes, has garnered much interest. EVs have pathophysiological properties in cancer, neurodegenerative disorders, infectious disease, and cardiovascular disease, highlighting possibilities not only for minimally invasive diagnostic applications but also for therapeutic interventions, like macromolecular drug delivery. Yet, in order to pursue therapies involving EVs and delivering their cargo, a better grasp of EV targeting is needed. Here, we review recent progress in understanding the molecular mechanisms underpinning EV uptake by receptor-ligand interactions with recipient cells, highlighting once again the overlap of EVs and viruses. Despite their highly heterogeneous nature, EVs require common viral entry pathways, and an unanticipated specificity for cargo delivery is being revealed. We discuss the challenges ahead in delineating specific roles for EV-associated ligands and cellular receptors.

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Virus entry at a glance

Cited by 213 publications

References 146 publications

Cell Surface THY-1 Contributes to Human Cytomegalovirus Entry via a Macropinocytosis-Like Process

Cell Surface THY-1 Contributes to Human Cytomegalovirus Entry via a Macropinocytosis-Like Process

Herpes Simplex Virus Internalization into Epithelial Cells Requires Na ⁺ /H ⁺ Exchangers and p21-Activated Kinases but neither Clathrin- nor Caveolin-Mediated Endocytosis

Extracellular Vesicles Exploit Viral Entry Routes for Cargo Delivery

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Virus entry at a glance

Cited by 213 publications

References 146 publications

Cell Surface THY-1 Contributes to Human Cytomegalovirus Entry via a Macropinocytosis-Like Process

Cell Surface THY-1 Contributes to Human Cytomegalovirus Entry via a Macropinocytosis-Like Process

Herpes Simplex Virus Internalization into Epithelial Cells Requires Na + /H + Exchangers and p21-Activated Kinases but neither Clathrin- nor Caveolin-Mediated Endocytosis

Extracellular Vesicles Exploit Viral Entry Routes for Cargo Delivery

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Herpes Simplex Virus Internalization into Epithelial Cells Requires Na ⁺ /H ⁺ Exchangers and p21-Activated Kinases but neither Clathrin- nor Caveolin-Mediated Endocytosis