The CD81 Partner EWI-2wint Inhibits Hepatitis C Virus Entry

Rocha-Perugini, Vera; Montpellier, Claire; Delgrange, David; Wychowski, Czeslaw; Helle, François; Pillez, André; Drobecq, Hervé; Naour, François Le; Charrin, Stéphanie; Levy, Shoshana; Rubinstein, Eric; Dubuisson, Jean; Cocquerel, Laurence

doi:10.1371/journal.pone.0001866

Cited by 106 publications

(121 citation statements)

References 48 publications

(91 reference statements)

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“…However, the expression of this molecule in non-hepatic cell lines does not lead to HCV entry, suggesting that additional molecule(s) regulate HCV cellular tropism. Very recently, Rocha-Perugini et al (42) have identified a cleavage product of EWI-2, referred to as EWI-2wint, which associates with CD81 and inhibits its interaction with the HCV envelope glycoproteins. Ectopic expression of this molecule in a hepatoma cell line susceptible to HCV infection blocked viral entry.…”

Section: Discussionmentioning

confidence: 99%

The Ig Domain Protein CD9P-1 Down-regulates CD81 Ability to Support Plasmodium yoelii Infection

Charrin

Yalaoui

Bartosch

et al. 2009

Journal of Biological Chemistry

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Invasion of hepatocytes by Plasmodium sporozoites is a prerequisite for establishment of a malaria natural infection. The molecular mechanisms underlying sporozoite invasion are largely unknown. We have previously reported that CD81 is required on hepatocytes for infection by Plasmodium falciparum and Plasmodium yoelii sporozoites. CD81 belongs to the tetraspanin superfamily of transmembrane proteins. By interacting with each other and with other transmembrane proteins, tetraspanins may play a role in the lateral organization of membrane proteins. In this study, we investigated the role of the two major molecular partners of CD81 in hepatocytic cells, CD9P-1/EWI-F and EWI-2, two transmembrane proteins belonging to a novel subfamily of immunoglobulin proteins. We show that CD9P-1 silencing increases the host cell susceptibility to P. yoelii sporozoite infection, whereas EWI-2 knock-down has no effect. Conversely, overexpression of CD9P-1 but not EWI-2 partially inhibits infection. Using CD81 and CD9P-1 chimeric molecules, we demonstrate the role of transmembrane regions in CD81-CD9P-1 interactions. Importantly, a CD9P-1 chimera that no longer associates with CD81 does not affect infection. Based on these data, we conclude that CD9P-1 acts as a negative regulator of P. yoelii infection by interacting with CD81 and regulating its function.Malaria remains the most important parasitic human disease, responsible for nearly one million deaths each year (1). Plasmodium natural infection is initiated by the inoculation of sporozoites in the host by a female Anopheles mosquito.Within the first hours of infection the motile sporozoites reach the liver and invade hepatocytes, where they further differentiate into a replicative exo-erythrocytic form (EEF) 5 that will ultimately give rise to thousands of merozoites that initiate the pathogenic erythrocytic cycle. Plasmodium sporozoites invade hepatocytes actively by forming a membrane-bound compartment called the parasitophorous vacuole (PV), where the parasite resides for further intracellular development (2, 3). The nature of the molecular interactions mediating sporozoite invasion still remains elusive. Two well-characterized sporozoite surface proteins, the circumsporozoite protein and the thrombospondin-related adhesive protein, are known to interact with the liver heparan sulfate proteoglycans (HSPGs) (2, 3). HSPGs play a role in the initial sequestration of the sporozoites in the liver sinusoids (4, 5), and activate sporozoites for productive invasion, leading to proteolytic processing of the circumsporozoite protein (6). Two sporozoite proteins, P36 and P36p/ P52, were shown to play a major role during infection of hepatocytes (7-9). Both belong to a Plasmodium-specific family characterized by the presence of domains with six conserved cysteines, but their precise function during sporozoite invasion and/or maintenance of the PV early after invasion remains unknown.To date, the only host molecule clearly identified as being essential for sporozoite invasion is CD81. ...

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Section: Discussionmentioning

confidence: 99%

The Ig Domain Protein CD9P-1 Down-regulates CD81 Ability to Support Plasmodium yoelii Infection

Charrin

Yalaoui

Bartosch

et al. 2009

Journal of Biological Chemistry

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“…Under these conditions, the purity checked by SDS-PAGE followed by Coomassie Blue staining was Ͼ95%. The PfI3 recombinant protein was further subjected to peptide mass fingerprint by MALDI-TOF mass spectrometry as described previously (35 13 C-labeled or not, as the nitrogen and carbon sources, respectively. For the wild type protein, purification was performed by heating the cell extract for 15 min at 75°C and centrifuging, followed by nickel-affinity chromatography (HiPrep Ni-NTA, GE Healthcare) on the supernatant.…”

Section: Methodsmentioning

confidence: 99%

Plasmodium falciparum Inhibitor-3 Homolog Increases Protein Phosphatase Type 1 Activity and Is Essential for Parasitic Survival

Fréville

Landrieu

García-Gimeno

et al. 2012

Journal of Biological Chemistry

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Background:Little is known about the regulators of phosphatase 1 enzyme activity in Plasmodium falciparum. Results: An activator, its binding motifs, and its nuclear location are presented. Reverse genetics show its essentiality for parasite survival. Conclusion:There is a potential link between this activator and the nuclear activity of this enzyme. Significance: This regulator is essential and can be considered as a potential drug target.

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“…25) and a truncated form of EWI-2 (ref. 26), respectively. The role of CD9 and CD81 in myogenesis and muscle regeneration has not been thoroughly investigated.…”

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confidence: 97%

Normal muscle regeneration requires tight control of muscle cell fusion by tetraspanins CD9 and CD81

et al. 2013

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Skeletal muscle regeneration after injury follows a remarkable sequence of synchronized events. However, the mechanisms regulating the typical organization of the regenerating muscle at different stages remain largely unknown. Here we show that muscle regeneration in mice lacking either CD9 or CD81 is abnormal and characterized by the formation of discrete giant dystrophic myofibres, which form more quickly in the absence of both tetraspanins. We also show that, in myoblasts, these two tetraspanins associate with the immunoglobulin domain molecule CD9P-1 (EWI-F/FPRP), and that grafting of CD9P-1-depleted myoblasts in regenerating muscles also leads to abnormal regeneration. In vitro myotubes lacking CD9P-1 or both CD9 and CD81 fuse with a higher frequency than normal myotubes. Our study unveils a mechanism preventing inappropriate fusion of myotubes that has an important role in the restitution of normal muscle architecture during muscle regeneration.

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The CD81 Partner EWI-2wint Inhibits Hepatitis C Virus Entry

Cited by 106 publications

References 48 publications

The Ig Domain Protein CD9P-1 Down-regulates CD81 Ability to Support Plasmodium yoelii Infection

The Ig Domain Protein CD9P-1 Down-regulates CD81 Ability to Support Plasmodium yoelii Infection

Plasmodium falciparum Inhibitor-3 Homolog Increases Protein Phosphatase Type 1 Activity and Is Essential for Parasitic Survival

Normal muscle regeneration requires tight control of muscle cell fusion by tetraspanins CD9 and CD81

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