Dominant-Negative FADD Rescues the In Vivo Fitness of a Cytomegalovirus Lacking an Antiapoptotic Viral Gene

Čičin‐Šain, Luka; Ruzsics, Zsolt; Podlech, Juergen; Bubić, Ivan; Ménard, Carine; Jonjić, Stipan; Reddehase, Matthias J.; Koszinowski, Ulrich H.

doi:10.1128/jvi.01803-07

Cited by 56 publications

(103 citation statements)

References 49 publications

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“…While M36 is thought to inhibit caspase-8 activation by binding to procaspase 8 (20,21), MC159 is thought to exert its inhibitory effect primarily by binding to FADD and preventing recruitment of procaspase 8 to the death-inducing signaling complex (DISC) (51) or oligomerization of the DISC (52). Remarkably, a previous study has shown that the loss of M36 is almost completely rescued by dominant negative FADD, which was overexpressed by using a strong heterologous promoter (24). Our results suggest that the inhibitory activity of MC159 or its expression level is insufficient for a complete reversal of the ⌬M36 phenotype in infected macrophages.…”

Section: Discussionmentioning

confidence: 60%

“…It is also conceivable that M36 has an additional function (besides inhibiting death receptor-dependent apoptosis) not shared by MC159. This hypothesis, however, seems unlikely, as dominant negative FADD rescued the replication defect in macrophages (24).…”

Section: Discussionmentioning

confidence: 99%

“…1B), it is well established that M45-deficient MCMV mutants do not replicate in SVEC4-10 endothelial cells due to necrosis induction (26,29). It has also been shown that M36-deficient mutants have a severe replication defect in different macrophage lines (21,24). Therefore, we tested, using our substitution mutants, whether MC159 could rescue these replication defects.…”

Section: Mc159 Inhibits Apoptosis But Does Not Block Necroptosis In Mmentioning

confidence: 99%

“…An MCMV ⌬M36 mutant was attenuated in vivo as shown by reduced virus titers in salivary glands and lung (24). Replication of the ⌬M36 virus was rescued in cultured macrophages and in vivo by insertion of a dominant negative FADD into the viral genome, suggesting that inhibition of death receptor-dependent apoptosis is important for MCMV replication and dissemination (24,25).…”

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confidence: 95%

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Functional Comparison of Molluscum Contagiosum Virus vFLIP MC159 with Murine Cytomegalovirus M36/vICA and M45/vIRA Proteins

Hüttmann

Krause

Schommartz

et al. 2016

J Virol

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Molluscum contagiosum virus (MCV) gene IMPORTANCEMCV is a human-pathogenic poxvirus that cannot be propagated in cell culture or laboratory animals. Therefore, MCV gene products have been studied predominantly in cells expressing individual viral genes. In this study, we analyzed the function of the MCV gene MC159 by expressing it from a different virus and comparing its functions to those of two well-characterized MCMV genes. In this system, MC159 displayed some but not all of the previously described functions, suggesting that the functions of a viral gene depend on the conditions under which it is expressed. Until a cell culture system for the analysis of MCV becomes available, it might be necessary to analyze MCV genes in several different systems to extrapolate their biological importance. Molluscum contagiosum virus (MCV) is a worldwide-occurring poxvirus that replicates exclusively in humans (1). Seroprevalence ranges from up to 39% in immunocompetent individuals (2, 3), affecting mostly children and young adults, to 91% in HIV-infected patients (2). Molluscum contagiosum (MC) is an infectious disease of the skin characterized by small, benign papular skin lesions that usually regress after a few months. However, in immunocompromised patients MC can become much more severe, with extensive lesions that are difficult to treat (1). This indicates the important role of the host immune system in confining and eliminating the infection.Despite its importance as a human pathogen, MCV has not been studied extensively due to technical difficulties. There is neither a cell culture system suitable for the propagation of MCV nor an animal model that recapitulates MCV replication. Therefore, individual MCV genes were studied either by using transient transfection or by expression in a recombinant vaccinia virus (VACV) as a surrogate virus (4).MCV expresses several immune-modulating proteins that are thought to contribute to the persistence of the virus (4, 5). One of these proteins, MC159, has been identified as a viral FLICE-like inhibitory protein (vFLIP) (6) due to its structural and functional similarity to cellular FLIP (cFLIP) (7). Although vFLIPs have not been found in poxviruses other than MCV, they are present in several gammaherpesviruses (6,8,9). MC159 interacts with Fasassociated protein with death domain (FADD) and procaspase-8 (formerly known as FADD-like interleukin-1␤-converting enzyme [FLICE]) and prevents Fas-and tumor necrosis factor alpha (TNF-␣)-induced apoptosis (6,(8)(9)(10). However, if caspase-8 is inhibited, receptor interacting protein kinase 1 (RIP1, RIPK1) is not cleaved and recruits RIP3 (RIPK3), initiating a pathway lead-

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Mc159 Inhibits Apoptosis But Does Not Block Necroptosis In Mmentioning

confidence: 99%

mentioning

confidence: 95%

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Functional Comparison of Molluscum Contagiosum Virus vFLIP MC159 with Murine Cytomegalovirus M36/vICA and M45/vIRA Proteins

Hüttmann

Krause

Schommartz

et al. 2016

J Virol

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“…Thus, m38.5 provides the function of the unrelated HCMV UL37 exon 1 (UL37x1) (9, 51) while, on the other hand, UL45 lacks the M45-encoded protein-protein interaction domain required to inhibit cell death signaling of receptor-interacting proteins (RIP) (89, 90). Evidence thus far indicates that the CMV-common gene products M36 and UL36 prevent cell death by a conserved mechanism (51,54,57,73), prompting the current evaluation of UL36 in differentiated macrophages.M36-deficient viruses are severely debilitated in vivo and induce apoptosis of tissue macrophages (17,18). In vitro studies indicated that M36-deficient virus replicates in fibroblasts or endothelial cells but not macrophage cell lines (57), results that may contribute to replication in some organs of the in-* Corresponding author.…”

mentioning

confidence: 99%

The Human Cytomegalovirus UL36 Gene Controls Caspase-Dependent and -Independent Cell Death Programs Activated by Infection of Monocytes Differentiating to Macrophages

McCormick

Roback

Livingston-Rosanoff

et al. 2010

J Virol

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The cellular protease caspase-8 activates extrinsic apoptosis and also functions to promote monocyteto-macrophage differentiation. Differentiation-induced alterations to antiviral caspase-8-dependent cell death pathways are unclear. Here, we show THP-1 monocyte-to-macrophage differentiation alters the specific cell death pathways activated in response to human cytomegalovirus (HCMV) infection. Employing viruses with mutations in UL36, the gene that encodes the viral inhibitor of caspase-8 activation (vICA), our data indicate that both caspase-dependent and -independent death pathways are activated in response to infection. Activation of caspase-dependent and -independent cell death responses restricted growth of vICA-deficient viruses, and vICA/pUL36 inhibited either response. Thus, these studies also reveal that the UL36 gene controls a caspase-independent cell death pathway. The impact of caspases on control of antiviral responses differed at early and late stages of macrophage differentiation. Early in differentiation, vICA-deficient virus-induced cell death was dependent on caspases and inhibited by the pan-caspase inhibitor z-VAD(OMe)-fluoromethyl ketone. In contrast, virus-induced death at late times of differentiation was caspase independent. Additional unlabeled and fluorescent inhibitors indicated that caspase-8 promoted death from within infected cells at early but not late stages of differentiation. These data highlight the multifunctional role of vICA/pUL36 as HCMV encounters various antiviral responses during macrophage differentiation.Based on the frequency of infected cells in patients with disseminated disease, monocytes and monocyte-derived macrophages are important to the pathogenesis of human cytomegalovirus (HCMV) (8,24,32). Further, peripheral blood monocytes and granulocyte-macrophage progenitors are suggested to be latent reservoirs as healthy seropositive individuals carry HCMV DNA in these cells, a result consistent with the maintenance of latent genomes within experimentally infected progenitors (6,37,38,58,72,76,79,80). Infected monocytes do not produce new virus; however, replication follows monocyte-macrophage differentiation whether induced by growth or proinflammatory cytokines or allogeneic stimulation. Evidence suggests that monocyte infections promote differentiation to a permissive, proinflammatory macrophage (14, 74). Thus, the production of new progeny is highly dependent on cellular differentiation. Monocytes, cells undergoing macrophage differentiation, and mature macrophages differ in the expression patterns of specific genes, including those important to cell death control (44, 49). Whether any change in expression of cell death control genes influences cell death pathways activated by HCMV infection is unclear. The current study addresses this question by evaluating the requirement for one viral cell death suppressor during productive infection of monocytes at different stages of macrophage differentiation.HCMV and the related murine cytomegalovirus (MCMV) encode several...

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Programmed Necrosis in Host Defense

Mocarski

2023

Current Topics in Microbiology and Immunology

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Dominant-Negative FADD Rescues the In Vivo Fitness of a Cytomegalovirus Lacking an Antiapoptotic Viral Gene

Cited by 56 publications

References 49 publications

Functional Comparison of Molluscum Contagiosum Virus vFLIP MC159 with Murine Cytomegalovirus M36/vICA and M45/vIRA Proteins

Functional Comparison of Molluscum Contagiosum Virus vFLIP MC159 with Murine Cytomegalovirus M36/vICA and M45/vIRA Proteins

The Human Cytomegalovirus UL36 Gene Controls Caspase-Dependent and -Independent Cell Death Programs Activated by Infection of Monocytes Differentiating to Macrophages

Programmed Necrosis in Host Defense

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