Tovilovic, Gordana (8612798200)Gordana (8612798200)TovilovicRistic, Biljana (7006688884)Biljana (7006688884)RisticSiljic, Marina (55428134900)Marina (55428134900)SiljicNikolic, Valentina (7102074128)Valentina (7102074128)NikolicKravic-Stevovic, Tamara (35275295500)Tamara (35275295500)Kravic-StevovicDulovic, Marija (52163312700)Marija (52163312700)DulovicMilenkovic, Marina (55308661500)Marina (55308661500)MilenkovicKnezevic, Aleksandra (22034890600)Aleksandra (22034890600)KnezevicBosnjak, Mihajlo (55763472000)Mihajlo (55763472000)BosnjakBumbasirevic, Vladimir (6603957757)Vladimir (6603957757)BumbasirevicStanojevic, Maja (57828665700)Maja (57828665700)StanojevicTrajkovic, Vladimir (7004516866)Vladimir (7004516866)Trajkovic2025-07-022025-07-022013https://doi.org/10.1016/j.micinf.2013.04.012https://www.scopus.com/inward/record.uri?eid=2-s2.0-84880618303&doi=10.1016%2fj.micinf.2013.04.012&partnerID=40&md5=5ba1387f94b0877467960fa6b7bd7b08https://remedy.med.bg.ac.rs/handle/123456789/13770We investigated the role of autophagy, a stress-inducible lysosomal self-digestion of cellular components, in modulation of herpes simplex virus type 1 (HSV-1)-triggered death of U251 human glioma cells. HSV-1 caused apoptotic death in U251 cells, characterized by phosphatidylserine externalization, caspase activation and DNA fragmentation. HSV-1-induced apoptosis was associated with the induction of autophagic response, as confirmed by the conversion of cytosolic LC3-I to autophagosome-associated LC3-II, increase in intracellular acidification, presence of autophagic vesicles, and increase in proteolysis of the selective autophagic target p62. HSV-1-triggered autophagy was not associated with the significant increase in the expression of proautophagic protein beclin-1 or downregulation of the major autophagy suppressor mammalian target of rapamycin (mTOR). Moreover, the phosphorylation of mTOR and its direct substrate p70 S6 kinase was augmented by HSV-1 infection, while the mTOR stimulator Akt and inhibitor AMPK-activated protein kinase (AMPK) were accordingly activated and suppressed, respectively. An shRNA-mediated knockdown of the autophagy-essential LC3β, as well as pharmacological inhibition of autophagy with bafilomycin A1 or 3-methyladenine, markedly accelerated apoptotic changes and ensuing cell death in HSV-1-infected glioma cells. These data indicate that AMPK/Akt/mTOR-independent autophagy could prolong survival of HSV-1-infected U251 glioma cells by counteracting the coinciding apoptotic response. © 2013 Institut Pasteur.AktAMP-activated protein kinaseApoptosisAutophagyHSV-1MTOR