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Virology. 2014 Mar;452-453:175-190. doi: 10.1016/j.virol.2014.01.008. Epub 2014 Feb 5.

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

Author information

1
Department of Biology, Queens College and Graduate Center of the City University of New York, 65-30 Kissena Boulevard, Flushing, NY 11367, USA.
2
Department of Technology and Health, Instituto Superiore di Sanita, Viale Regina Elena 299, 00161 Rome, Italy.
3
Department of Drug Research and Evaluation, Instituto Superiore di Sanita, Viale Regina Elena 299, 00161 Rome, Italy.
4
San Raffaele Institute Sulmona, 67039 L'Aquila, Italy.
5
Department of Microbiology, Division of Infectious Diseases, Mount Sinai School of Medicine, New York, NY 10029, USA.
6
Global Health and Emerging Pathogens Institute, Division of Infectious Diseases, Mount Sinai School of Medicine, New York, NY 10029, USA.
#
Contributed equally

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.

KEYWORDS:

Apoptosis; Autophagy; Cell death; Influenza; Rapamycin; Torin1; mTORC1/2; p70S6K

PMID:
24606695
PMCID:
PMC4005847
DOI:
10.1016/j.virol.2014.01.008
[Indexed for MEDLINE]
Free PMC Article

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