Control of apoptosis in influenza virus-infected cells by up-regulation of Akt and p53 signaling.
PI3k-Akt and p53 pathways are known to play anti- and pro-apoptotic roles in cell death, respectively. Whether these pathways are recruited in influenza virus infection in highly productive monkey (CV-1) and canine (MDCK) kidney cells was studied here. Phosphorylation of Akt (Akt-pho) was found to occur only early after infection (5-9 h.p.i). Nuclear accumulation and phosphorylation of p53 (p53-pho), and expression of its natural target p21/waf showed low constitutive levels at this period, whereas all three parameters were markedly elevated at the late apoptotic stage (17-20 h.p.i.). Up-regulation of Akt-pho and p53-pho was not induced by UV-inactivated virus suggesting that it required virus replication. Also, mRNAs of p53 and its natural antagonist mdm2 were not increased throughout infection indicating that p53-pho was up-regulated by posttranslational mechanisms. However, p53 activation did not seem to play a leading role in influenza-induced cell death: (i) infection of CV1 and MDCK cells with recombinant NS1-deficient virus provoked accelerated apoptotic death characterized by the lack of p53 activation; (ii) mixed apoptosis-necrosis death developed in influenza-infected human bronchial H1299 cells carrying a tetracycline-regulated p53 gene did not depend on p53 gene activation by tetracycline. Virus-induced apoptosis and signaling of Akt and p53 developed in IFN-deficient VERO cells with similar kinetics as in IFN-competent CV1-infected cells indicating that these processes were endocrine IFN-independent. Apoptosis in influenza-infected CV-1 and MDCK cells was Akt-dependent and was accelerated by Ly294002, a specific inhibitor of PI3k-Akt signaling, and down-regulated by the viral protein NS1, an inducer of host Akt. The obtained data suggest that influenza virus (i) initiates anti-apoptotic PI3k-Akt signaling at early and middle phases of infection to protect cells from fast apoptotic death and (ii) provokes both p53-dependent and alternative p53-independent apoptotic and/or necrotic (in some host systems) cell death at the late stage of infection.
Zhirnov
Oleg P
OP
D.I. Ivanovsky Institute of Virology, Moscow 123098, Russia. zhirnov@inbox.ru
Klenk
Hans-Dieter
HD
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D006801:Humans; D008954:Models, Biological; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D009975:Orthomyxoviridae; D009976:Orthomyxoviridae Infections / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation; D014709:Vero Cells; D017361:Viral Nonstructural Proteins / Q000235:genetics
C085820:INS1 protein, influenza virus; D016159:Tumor Suppressor Protein p53; D017361:Viral Nonstructural Proteins; D051058:Oncogene Protein v-akt