Apoptosis induced by Semliki Forest virus is RNA replication dependent and mediated via Bak

Urban, Christian; Rhême, C; Berg, B. M. M. Van Den; Pick, Robert; Nitschke, Roland; Borner, Christoph

doi:10.1038/cdd.2008.61

Cited by 27 publications

(46 citation statements)

References 40 publications

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“…4B). A role for BAK in DC apoptosis triggered by microbial stimuli as well as by IFN-b has not been described before, but a central role for BAK in IFN-a-mediated and Semliki Forest virus-mediated apoptosis has been reported in other cellular systems (45,46). Extending these notions, BAK may also regulate apoptosis in immature DCs, as suggested by our Western blot analysis (Fig.…”

Section: Discussionsupporting

confidence: 62%

Autocrine TNF Is Critical for the Survival of Human Dendritic Cells by Regulating BAK, BCL-2, and FLIPL

Lehner

Kellert

Proff

et al. 2012

The Journal of Immunology

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The life span of dendritic cells (DCs) is determined by the balance of pro- and antiapoptotic proteins. In this study, we report that serum-free cultured human monocyte-derived DCs after TLR stimulation with polyinosinic acid-polycytidylic acid or LPS underwent apoptosis, which was correlated with low TNF production. Apoptosis was prevented by the addition of exogenous TNF or by concomitant stimulation with R-848, which strongly amplified endogenous TNF production. Neutralization of TNF confirmed that DC survival was mediated by autocrine TNF induced either by stimulation with R-848 or by ligation of CD40. DCs stimulated by polyinosinic acid-polycytidylic acid or IFN-β, another known inducer of DC apoptosis, were characterized by high levels and activation of the proapoptotic protein BAK. The ratio of antiapoptotic BCL-2 to BAK correlated best with the survival of activated DCs. Addition of TNF increased this ratio but had little effect on BAX and XIAP. Knockdown experiments using small interfering RNAs confirmed that the survival of activated and also of immature DCs was regulated by BAK and showed that TNF was protective only in the presence of FLIPL. Together, our data demonstrate that the survival of DCs during differentiation and activation depends on autocrine TNF and that the inhibition of BAK plays an important role in this process.

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Section: Discussionsupporting

confidence: 62%

Autocrine TNF Is Critical for the Survival of Human Dendritic Cells by Regulating BAK, BCL-2, and FLIPL

Lehner

Kellert

Proff

et al. 2012

The Journal of Immunology

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“…Several RNA viruses (measles virus, vesicular stomatitis virus, Sindbis virus, and vaccinia virus, among others) induce apoptosis via mechanisms involving receptor binding and internalization or other replication events (8,12,15,19,21,22,26,41,48). Alternatively, some DNA viruses (Epstein-Barr virus and papillomavirus 16) inhibit programmed cell death by inducing the expression of cellular IAP (1, 10).…”

Section: Discussionmentioning

confidence: 99%

Apoptosis in Murine Norovirus-Infected RAW264.7 Cells Is Associated with Downregulation of Survivin

Bok

Prikhodko

Green

et al. 2009

J Virol

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Noroviruses (NVs) are recognized as a major cause of nonbacterial gastroenteritis in humans. Studies of the human NVs continue to be hampered by the inability to propagate them in any cell culture system. Until recently, most data concerning NV replication were derived from studies of feline calicivirus and rabbit hemorrhagic disease virus, which are cultivable members of the family Caliciviridae. From such studies, it was proposed that caliciviruses induce apoptosis to facilitate the dissemination of viral progeny in the host. The discovery that MNV type 1 (MNV-1) grows in RAW264.7 cells provided the first cell culture system for use in studying the role of apoptosis in NV infection. We first showed that MNV-1 replication triggered apoptosis in infected RAW264.7 cells and then demonstrated that cell death was associated with activation of caspase-9 and caspase-3 through the mitochondrial pathway. This process was dependent on virus replication, since inactivated virus failed to induce signs of apoptosis. In order to better understand the apoptotic process induced by MNV-1 infection of RAW264.7 cells, we investigated the expression profiles of MNV-1-infected versus mockinfected cells. Survivin, a member of the inhibitor of apoptosis protein family, was found to be significantly downregulated in an inverse relationship with the virus genome replication. This study showed that, unlike other viruses that upregulate survivin, MNV-1 is the first virus found to downregulate the levels of survivin. We observed that MNV-1 replication in RAW264.7 cells activated caspases, resulting in apoptosis through the mitochondrial pathway, possibly as a result of downregulation of survivin.

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“…SINV-induced apoptosis does not appear to require virus replication; the entry of UV-inactivated virus into a cell can trigger ceramide release and cell death (36,37). In contrast, UV-inactivated SFV does not kill cells (86). SFV genome replication without structural protein expression is sufficient to kill cells (29,86).…”

mentioning

confidence: 99%

“…In contrast, UV-inactivated SFV does not kill cells (86). SFV genome replication without structural protein expression is sufficient to kill cells (29,86). A number of alphavirus mutants with reduced cytopathogenicity have mutations in nsP2, and the expression of nsP2 alone is cytotoxic (15,20,21,25,26,30,63,80).…”

mentioning

confidence: 99%

Semliki Forest Virus-Induced Endoplasmic Reticulum Stress Accelerates Apoptotic Death of Mammalian Cells

Barry

Atkinson

Ferguson

et al. 2010

J Virol

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The alphavirus Semliki Forest virus (SFV) and its derived vectors induce apoptosis in mammalian cells.Here, we show that apoptosis is associated with the loss of mitochondrial membrane potential followed by the activation of caspase-3, caspase-8, and caspase-9. Cell death can be partially suppressed by treatment with the pan-caspase inhibitor zVAD-fmk. To determine the role of SFV structural proteins in cell death, the temporal course of cell death was compared in cells infected with SFV and cells infected with SFV virus replicon particles (VRPs) lacking some or all of the virus structural genes. In the absence of virus structural proteins, cell death was delayed. The endoplasmic reticulum (ER) stress response, as determined by the splicing of X-box binding protein 1 (XBP1) transcripts and the activation of caspase-12, was activated in virus-infected cells but not in VRP (SFV lacking structural genes)-infected cells. The C/EBP-homologous protein (CHOP) was upregulated by both virus and VRP infections. The virus envelope proteins but not the virus capsid protein triggered ER stress. These results demonstrate that in NIH 3T3 cells, SFV envelope glycoproteins trigger the unfolded protein response of the ER and accelerate apoptotic cell death initiated by virus replicase activity.

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Apoptosis induced by Semliki Forest virus is RNA replication dependent and mediated via Bak

Cited by 27 publications

References 40 publications

Autocrine TNF Is Critical for the Survival of Human Dendritic Cells by Regulating BAK, BCL-2, and FLIPL

Autocrine TNF Is Critical for the Survival of Human Dendritic Cells by Regulating BAK, BCL-2, and FLIPL

Apoptosis in Murine Norovirus-Infected RAW264.7 Cells Is Associated with Downregulation of Survivin

Semliki Forest Virus-Induced Endoplasmic Reticulum Stress Accelerates Apoptotic Death of Mammalian Cells

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