Mechanisms of Syncytial Fusion: A Review

Pötgens, Andy J.G.; Schmitz, Ulrike; Bose, Patrick; Versmold, A.; Kaufmann, Peter; Frank, Hans-Georg

doi:10.1053/plac.2002.0772

Cited by 123 publications

(63 citation statements)

References 59 publications

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“…These results contrast markedly with studies of the physiological syncytium formation that occurs during such cellular processes as the formation of syncytiotrophoblasts, myotubes, and osteoclasts (32,48,49,58). In these cases of virus-independent syncytium formation, cell-cell fusion is the result of specific differentiation pathways.…”

Section: Discussioncontrasting

confidence: 59%

Extensive Syncytium Formation Mediated by the Reovirus FAST Proteins Triggers Apoptosis-Induced Membrane Instability

Salsman

Top

Boutilier

et al. 2005

J Virol

104

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The fusion-associated small transmembrane (FAST) proteins of the fusogenic reoviruses are the only known examples of membrane fusion proteins encoded by nonenveloped viruses. While the involvement of the FAST proteins in mediating extensive syncytium formation in virus-infected and -transfected cells is well established, the nature of the fusion reaction and the role of cell-cell fusion in the virus replication cycle remain unclear. To address these issues, we analyzed the syncytial phenotype induced by four different FAST proteins: the avian and Nelson Bay reovirus p10, reptilian reovirus p14, and baboon reovirus p15 FAST proteins. Results indicate that FAST protein-mediated cell-cell fusion is a relatively nonleaky process, as demonstrated by the absence of significant [ 3 H]uridine release from cells undergoing fusion and by the resistance of these cells to treatment with hygromycin B, a membrane-impermeable translation inhibitor. However, diminished membrane integrity occurred subsequent to extensive syncytium formation and was associated with DNA fragmentation and chromatin condensation, indicating that extensive cell-cell fusion activates apoptotic signaling cascades. Inhibiting effector caspase activation or ablating the extent of syncytium formation, either by partial deletion of the avian reovirus p10 ectodomain or by antibody inhibition of p14-mediated cell-cell fusion, all resulted in reduced membrane permeability changes. These observations suggest that the FAST proteins do not possess intrinsic membrane-lytic activity. Rather, extensive FAST protein-induced syncytium formation triggers an apoptotic response that contributes to altered membrane integrity. We propose that the FAST proteins have evolved to serve a dual role in the replication cycle of these fusogenic nonenveloped viruses, with nonleaky cell-cell fusion initially promoting localized cell-cell transmission of the infection followed by enhanced progeny virus release from apoptotic syncytia and systemic dissemination of the infection.The reovirus fusion-associated small transmembrane (FAST) protein family is comprised of an atypical group of membrane fusion proteins encoded by nonenveloped viruses. Different FAST proteins have been isolated from four of the five recognized species in the genus Orthoreovirus, family Reoviridae (16). These fusogenic reoviruses and their corresponding FAST proteins include the p10 homologues encoded by avian reovirus (ARV) and Nelson Bay reovirus (NBV), p15 from baboon reovirus (BRV), and p14 from reptilian reovirus (RRV) (12,14,53). Unlike the membrane fusion proteins encoded by enveloped viruses, the reovirus FAST proteins are nonstructural viral proteins and therefore are not involved in virus entry (14,15,53). Rather, these proteins are expressed in virus-infected cells and trafficked through the endoplasmic reticulum-Golgi pathway to the plasma membrane (52). Accumulation of the FAST proteins at the cell surface leads to fusion of virus-infected cells with neighboring uninfected cells, in both cell cultu...

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Section: Discussioncontrasting

confidence: 59%

Extensive Syncytium Formation Mediated by the Reovirus FAST Proteins Triggers Apoptosis-Induced Membrane Instability

Salsman

Top

Boutilier

et al. 2005

J Virol

104

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“…After initial reports about the transdifferentiation of BMDCs into nonhematopoietic cell types in vitro and in vivo, cell fusion has been suggested as the main mechanism behind the observed plasticity of BMDCs (Alvarez-Dolado, 2007). Endogenous cell fusion has been discussed in different contexts, including physiological mechanisms like spermatozoa-ovum fusion, developmental processes like the formation of placenta, bone, and muscle (Potgens et al, 2002;Horsley and Pavlath, 2004;Chen et al, 2007), but also in the context of pathological processes like virus-induced fusion (Price et al, 1988) and tumorigenesis (Bjerkvig et al, 2005). All previous studies dealing with the investigation of fusion events in adult animals have used experimental procedures such as cell transplantation after lethal irradiation, transplantation of cells from syngeneic mice, or parabiotic models to generate chimerism (Wagers et al, 2002;Massengale et al, 2005;Magrassi et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Fusion of Hematopoietic Cells with Purkinje Neurons Does Not Lead to Stable Heterokaryon Formation under Noninvasive Conditions

Nern

Wolff²,

Macas³

et al. 2009

J. Neurosci.

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Transplanted hematopoietic cells have previously been shown to contribute to cells of other tissues by cell fusion. We wanted to elucidate whether this phenomenon of cell fusion also occurs under physiological conditions. Using a transgenic mouse reporter system to irreversibly label cells of the hematopoietic lineage, we were able to test their contribution to other tissues in the absence of any additional and potentially confounding factors such as irradiation or chemoablation. We found genetically marked, fused Purkinje neurons as well as hepatocytes in numbers comparable to previous bone marrow transplantation studies. The number of fused Purkinje neurons increased after intrathecal administration of bacterial lipopolysaccharide, suggesting that cell fusion can be induced by inflammation. In contrast to previous studies, however, genetically labeled Purkinje neurons never contained more than one nucleus, and we found only a single cell containing two Y-chromosomes in a male mouse. Consistent with results from the mouse model and unlike human bone marrow transplant recipients, postmortem adult human cerebelli of nontransplanted individuals were devoid of binucleated or polyploid Purkinje neurons. Therefore, our data suggests that fusion of hematopoietic cells with Purkinje neurons is only transient and does not lead to stable heterokaryon formation under noninvasive conditions.

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“…Its presence may simply reflect the presence of remnant surface membranes left over from the fusion of mononuclear cytotrophoblasts to multinucleated syncytiotrophoblasts during normal villous trophoblast differentiation (27,28). The syncytiotrophoblast is the only syncytial epithelium in humans.…”

Section: Discussionmentioning

confidence: 99%

Targeting and crossing of the human maternofetal barrier byListeria monocytogenes: Role of internalin interaction with trophoblast E-cadherin

Lecuit

Nelson

Smith

et al. 2004

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

213

183

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Listeria monocytogenes produces severe fetoplacental infections in humans. How it targets and crosses the maternofetal barrier is unknown. We used immunohistochemistry to examine the location of L. monocytogenes in placental and amniotic tissue samples obtained from women with fetoplacental listeriosis. The results raised the possibility that L. monocytogenes crosses the maternofetal barrier through the villous syncytiotrophoblast, with secondary infection occurring via the amniotic epithelium. Because epidemiological studies indicate that the bacterial surface protein, internalin (InlA), may play a role in human fetoplacental listeriosis, we investigated the cellular patterns of expression of its host receptor, E-cadherin, at the maternofetal interface. E-cadherin was found on the basal and apical plasma membranes of syncytiotrophoblasts and in villous cytotrophoblasts. Established trophoblastic cell lines, primary trophoblast cultures, and placental villous explants were each exposed to isogenic InlA؉ or InlA؊ strains of L. monocytogenes, and to L. innocua expressing or not InlA. Quantitative assays of cellular invasion demonstrated that bacterial entry into syncytiotrophoblasts occurs via the apical membrane in an InlA-E-cadherin dependent manner. In human placental villous explants, bacterial invasion of the syncytiotrophoblast barrier and underlying villous tissue and subsequent replication produces histopathological lesions that mimic those seen in placentas of women with listeriosis. Thus, the InlA-E-cadherin interaction that plays a key role in the crossing of the intestinal barrier in humans is also exploited by L. monocytogenes to target and cross the placental barrier. Such a ligand-receptor interaction allowing a pathogen to specifically cross the placental villous trophoblast barrier has not been reported previously.

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Mechanisms of Syncytial Fusion: A Review

Cited by 123 publications

References 59 publications

Extensive Syncytium Formation Mediated by the Reovirus FAST Proteins Triggers Apoptosis-Induced Membrane Instability

Extensive Syncytium Formation Mediated by the Reovirus FAST Proteins Triggers Apoptosis-Induced Membrane Instability

Fusion of Hematopoietic Cells with Purkinje Neurons Does Not Lead to Stable Heterokaryon Formation under Noninvasive Conditions

Targeting and crossing of the human maternofetal barrier byListeria monocytogenes: Role of internalin interaction with trophoblast E-cadherin

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