The Major Apoptotic Pathway Activated and Suppressed by Poliovirus

Abstract

Cells respond to poliovirus infection by switching on the apoptotic program, implementation of which is usually suppressed by viral antiapoptotic functions. We show here that poliovirus infection of HeLa cells or derivatives of MCF-7 cells was accompanied by the efflux of cytochrome c from mitochondria. This efflux occurred during both abortive infection (e.g., interrupted by guanidine-HCl and ending with apoptosis) and productive infection (leading to cytopathic effect). The former type of infection, but not the latter, was accompanied by truncation of the proapoptotic protein Bid. The virus-triggered cytochrome c efflux was suppressed by overexpression of Bcl-2. Both abortive and productive infections also resulted in a decreased level of procaspase-9, as revealed by Western blotting. In the former case, this decrease was accompanied by the accumulation of a protein with the electrophoretic mobility of active caspase-9. In contrast, in the productively infected cells, the latter protein was absent but caspase-9-related polypeptides with altered mobility could be detected. Both caspase-9 and caspase-3 were shown to be essential for the development of such hallmarks of virus-induced apoptosis as chromatin condensation, DNA degradation, and nuclear fragmentation. These and some other results suggest the following scenario. Poliovirus infection activates the apoptotic pathway, involving mitochondrial damage, cytochrome c efflux, and consecutive activation of caspase-9 and caspase-3. The apoptotic signal appears to be amplified by a loop which includes secondary processing of Bid. The implementation of the apoptotic program in productively infected cells may be suppressed, however, by the viral antiapoptotic functions, which act at a step(s) downstream of the cytochrome c efflux. The suppression appears to be caused, at least in part, by aberrant processing and degradation of procaspase-9.

Poliovirus Protein 3A Binds and Deregulates LIS1, Causing Block of Membrane Protein Trafficking and Deregulation of Cell Division

“…4 Effective replication of even the smallest mammalian RNA-containing viruses with very short life cycles, such as poliovirus (7-9 h), appeared to depend on the suppression of apoptosis. [5][6][7] We recently demonstrated that one of the mechanisms of apoptosis suppression during poliovirus infection involves rapid disappearance of a number of short-living receptors from the cell surface, including those for TNF, TRAIL and interferon, 8 making the infected cells less sensitive to these cytokines. This poliovirus function is exerted, at least in part, through 3A, a multifunctional viral protein that is involved in poliovirus RNA replication, 9 virus-induced rearrangement of cytoplasmic membrane structures, 10 and suppression of protein trafficking between the endoplasmic reticulum (ER) and Golgi apparatus, 11,12 an essential step in plasma membrane and secreted protein processing.…”

The CREB3-Herp signalling module limits the cytosolic calcium concentration increase and apoptosis induced by poliovirus

“…As previously reported by our group (Autret et al, 2007(Autret et al, , 2008Brisac et al, 2010) and by Agol's group (Agol et al, 2000;Belov et al, 2003), several series of events may be involved in the regulation of PV-induced apoptosis. The results presented here highlight a new pathway, the CREB/ Herp pathway, which plays an anti-apoptotic role.…”

“…The induction of apoptosis during PV infection is controlled by a balance between survival pathways early in infection, allowing completion of the viral cycle, and the progression to programmed cell death later in infection (Agol et al, 2000;Autret et al, 2008;Belov et al, 2003). In this study, we showed that the CREB3/Herp signalling pathway was involved in modulating this balanced regulation.…”

“…In a murine model, PV replication in the central nervous system (CNS) destroys motor neurons by triggering apoptosis (Girard et al, 1999). In neuronal cell lines, PVinduced apoptosis involves mitochondrial dysfunction (Belov et al, 2003;Gosselin et al, 2003). We have previously showed that this event was driven by a balance between pro-and anti-apoptotic signals: the JNK and PI3K pathways, respectively (Autret et al, 2007(Autret et al, , 2008.…”

The TLR3/TICAM-1 Pathway Is Mandatory for Innate Immune Responses to Poliovirus Infection

“…Second, MDA5 is degraded in PV-infected cells in a proteasome-and caspase-dependent manner, resulting in the lack of type I IFN production (29). Third, PV-mediated apoptosis occurs in a caspase-dependent manner to disable infected cells from inducing an IFN response (46), with the MDA5-dependent innate response to PV infection becoming minimal within 3 h postinfection. Additionally, RIG-I is also cleaved by the viral protease 3C (47), and additional RIG-I functions are subsequently disrupted.…”