mTOR-independent autophagy counteracts apoptosis in herpes simplex virus type 1-infected U251 glioma cells.

Abstract

We 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.

• Authors: Gordana Tovilovic, Biljana Ristic, Marina Siljic, Valentina Nikolic, Tamara Kravic-Stevovic, Marija Dulovic, Marina Milenkovic, Aleksandra Knezevic, Mihajlo Bosnjak, Vladimir Bumbasirevic, Maja Stanojevic, Vladimir Trajkovic
• Journal: Microbes and infection (Microbes Infect) 2013 Jul-Aug Vol. 15 Issue 8-9 Pg. 615-24 ISSN: 1769-714X [Electronic] France
• PMID: 23669212 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Chemical References

• MTOR protein, human
• TOR Serine-Threonine Kinases

Topics

• Apoptosis
• Autophagy
• Cell Line
• Cell Survival
• Gene Expression Regulation
• Herpesvirus 1, Human (immunology, pathogenicity)
• Host-Pathogen Interactions
• Humans
• Neuroglia (immunology, virology)
• TOR Serine-Threonine Kinases (metabolism)