mTOR/p70S6K signaling distinguishes routine, maintenance-level autophagy from autophagic cell death during influenza A infection

• Published in: Virology (New York, N.Y.) Vol. 452; pp. 175 - 190
• Main Authors: Datan, Emmanuel, Shirazian, Alireza, Benjamin, Shawna, Matassov, Demetrius, Tinari, Antonella, Malorni, Walter, Lockshin, Richard A, Garcia-Sastre, Adolfo, Zakeri, Zahra
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2014
• Subjects: Apoptosis; Autophagy; Cell death; Humans; Infectious Disease; Influenza; Influenza A virus; Influenza A virus - genetics; Influenza A virus - physiology; Influenza, Human - enzymology; Influenza, Human - genetics; Influenza, Human - physiopathology; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; mTORC1/2; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; p70S6K; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Rapamycin; Ribosomal Protein S6 Kinases, 70-kDa - genetics; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Signal Transduction; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Torin1; p70S6K; Cell death; Influenza; mTORC1/2; Rapamycin; Autophagy; Torin1; Apoptosis
• ISSN: 0042-6822; 1096-0341
• DOI: 10.1016/j.virol.2014.01.008

Abstract Autophagy, a stress response activated in influenza A virus infection helps the cell avoid apoptosis. However, in the absence of apoptosis infected cells undergo vastly expanded autophagy and nevertheless die in the presence of necrostatin but not of autophagy inhibitors. Combinations of inhibitors indicate that the controls of protective and lethal autophagy are different. Infection that triggers apoptosis also triggers canonical autophagy signaling exhibiting transient PI3K and mTORC1 activity. In terminal autophagy phospho-mTOR(Ser2448) is suppressed while mTORC1, PI3K and mTORC2 activities increase. mTORC1 substrate p70S6K becomes highly phosphorylated while its activity, now regulated by mTORC2, is required for LC3-II formation. Inhibition of mTORC2/p70S6K, unlike that of PI3K/mTORC1, blocks expanded autophagy in the absence of apoptosis but not moderate autophagy. Inhibitors of expanded autophagy limit virus reproduction. Thus expanded, lethal autophagy is activated by a signaling mechanism different from autophagy that helps cells survive toxic or stressful episodes.