Early Phosphatidylinositol 3-Kinase/Akt Pathway Activation Limits Poliovirus-Induced JNK-Mediated Cell Death

Abstract

Poliovirus (PV)-induced apoptosis seems to play a major role in tissue injury in the central nervous system (CNS). We have previously shown that this process involves PV-induced Bax-dependent mitochondrial dysfunction mediated by early JNK activation in IMR5 neuroblastoma cells. We showed here that PV simultaneously activates the phosphatidylinositol 3-kinase (PI3K)/Akt survival signaling pathway in these cells, limiting the extent of JNK activation and thereby cell death. JNK inhibition is associated with PI3K-dependent negative regulation of the apoptosis signal-regulating kinase 1, which acts upstream from JNK in PV-infected IMR5 cells. In poliomyelitis, this survival pathway may limit the spread of PV-induced damage in the CNS.Poliovirus (PV), from the Picornaviridae family, causes paralytic poliomyelitis, a disease in which the motor neurons are destroyed in association with PV replication. PV consists of a single-stranded positive-sense RNA genome surrounded by a nonenveloped icosahedral protein capsid. The human PV receptor CD155 and its simian counterparts belong to the immunoglobulin superfamily (24,25,31) and are related to the nectin family of adhesion molecules (28,38).PV is transmitted mostly via the fecal-oral route. It first infects the oropharynx and the digestive tract and then spreads to the central nervous system (CNS), in which it targets mostly motor neurons. Studies with mouse models have shown that PV-infected motor neurons in the spinal cord die by apoptosis (10, 19). PV-induced apoptosis therefore seems to play a major role in the tissue injury occurring in the CNS.PV triggers apoptosis in vitro in tissue cultures of human colon carcinoma (Caco-2) cells (4), promonocytic cells (U937) (29), dendritic cells (41), murine L cells expressing CD155 (21, 36), HeLa cells (8,39), and cultures of mixed mouse primary nerve cells (12) from the cerebral cortexes of mice transgenic for CD155. Analyses of the apoptotic pathways induced following PV infection in several cell lines have demonstrated that mitochondria are key actors of PV-induced apoptosis. In particular, mitochondrial outer membrane permeabilization (MOMP) following PV infection leads to a loss of mitochondrial transmembrane potential and the release of proapoptotic molecules, including cytochrome c, from the mitochondria to the cytosol (8, 21). We recently demonstrated that MOMP in PV-infected neuronal IMR5 cells was dependent on Bax, a proapoptotic member of the Bcl-2 family. Bax activation was mediated by c-Jun NH2-terminal kinase (JNK) phosphorylation after PV infection (6). JNK activation occurred early after PV infection, whereas apoptotic features were observed later in PV-infected cells. These events may involve a balance between pro-and antiapoptotic signals following PV infection. Pro-and antiapoptotic events potentially acting in synergy or competing with each other during the reproduction cycle of PV have been described by Agol's group (1, 39). However, the mechanisms involved in maintaining this delicate balance remain uncle...

Cellular kinase inhibitors that suppress enterovirus replication have a conserved target in viral protein 3A similar to that of enviroxime

“…Individual treatment with these kinase inhibitors did not affect PV or EV71 infection, thus a synergy of these kinase inhibitors was essential for the inhibitory effect. This is consistent with a recent observation by Autret et al (2008) that PI3K/Akt signalling does not affect the growth of PV. In EMCV infection, wortmannin treatment even increased viral protein synthesis and the yield of virus (Svitkin et al, 1998).…”

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 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 apoptotic programme initiated by PV infection also involves calcium (Ca 2+ ) flux from the endoplasmic reticulum (ER) lumen to the cytosol, via the ER-resident Ca 2+ channels IP 3 R (inositol 1,4,5-triphosphate receptor) and RyR (ryanodine receptor) (Brisac et al, 2010).…”

Enhancing therapeutic efficacy by targeting non-oncogene addicted cells with combinations of signal transduction inhibitors and chemotherapy

“…It has been reported that the PI3K pathway can negatively regulate JNK. 66 Thus inhibition of PI3K may result in activation of JNK.…”