title: mTOR/p70S6K signaling distinguishes routine, maintenance-level autophagy from autophagic cell death during influenza A infection.
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.
authors.affiliation: Department of Biology, Queens College and Graduate Center of the City University of New York, 65-30 Kissena Boulevard, Flushing, NY 11367, USA.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Datan
authors.affiliation: Department of Biology, Queens College and Graduate Center of the City University of New York, 65-30 Kissena Boulevard, Flushing, NY 11367, USA.
authors.forename: Alireza
authors.initials: A
authors.lastname: Shirazian
authors.affiliation: Department of Biology, Queens College and Graduate Center of the City University of New York, 65-30 Kissena Boulevard, Flushing, NY 11367, USA.
authors.forename: Shawna
authors.initials: S
authors.lastname: Benjamin
authors.affiliation: Department of Biology, Queens College and Graduate Center of the City University of New York, 65-30 Kissena Boulevard, Flushing, NY 11367, USA.
authors.forename: Demetrius
authors.initials: D
authors.lastname: Matassov
authors.affiliation: Department of Technology and Health, Instituto Superiore di Sanita, Viale Regina Elena 299, 00161 Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Tinari
authors.affiliation: Department of Drug Research and Evaluation, Instituto Superiore di Sanita, Viale Regina Elena 299, 00161 Rome, Italy.|San Raffaele Institute Sulmona, 67039 L'Aquila, Italy.
authors.forename: Walter
authors.initials: W
authors.lastname: Malorni
authors.affiliation: Department of Biology, Queens College and Graduate Center of the City University of New York, 65-30 Kissena Boulevard, Flushing, NY 11367, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lockshin
authors.affiliation: Department of Microbiology, Division of Infectious Diseases, Mount Sinai School of Medicine, New York, NY 10029, USA.|Global Health and Emerging Pathogens Institute, Division of Infectious Diseases, Mount Sinai School of Medicine, New York, NY 10029, USA.|Global Health and Emerging Pathogens Institute, Division of Infectious Diseases, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Garcia-Sastre
authors.affiliation: Department of Biology, Queens College and Graduate Center of the City University of New York, 65-30 Kissena Boulevard, Flushing, NY 11367, USA.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Zakeri
mesh_terms: D017209:Apoptosis; D001343:Autophagy; D006801:Humans; D009980:Influenza A virus / Q000235:genetics / Q000502:physiology*; D007251:Influenza, Human / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases
keywords: Apoptosis; Autophagy; Cell death; Influenza; Rapamycin; Torin1; mTORC1/2; p70S6K